Syndrome X: case report DORIS KAVANAGH-GRAY, MD, FRCP[C], FACP, FACC
Transmural myocardial Infarction occurred In a 48-year-old woman with syndrome X - atypical angina pectorls and anglographically normal coronary arteries. Before the infarction her electrocardiogram had been normal at rest but showed lschemia after exercise. Angiography 3 months after infarction revealed a normal coronary tree but hypokinesla of the posterior left ventricular wall. Un infarctus transmural du myocarde est survenu chez une femme de 48 ans atteinte du syndrome X - une angine de poitrine atypique avec angiographie normale des artores coronalres. Avant l'infarctus Ia patlente avait un 6lectrocardiogramme normal au repos mals presentait des signes d'lsch6mle apr&s effort. Une angiographie pratiquee 3 mois apr.s I'lnfarctus a r6v616 un systeme coronaire normal mais une hypoklnesie de Ia paroi post6rleure du ventricule gauche. Angina pectoris in the presence of angiographically normal coronary arteries - "syndrome X" - is considered to have a good prognosis. In the case reported below a woman with syndrome X suffered a transmural myocardial infarction; a normal coronary tree was demonstrated by angiography before and after the event. Case report
was therefore interpreted as positive for ischemia. Coronary and left ventricular angiography was performed by Judkins' technique under meperkline and secobarbital sedation. Multiple views of both coronary arteries were obtained with both motion and still photography; no abnormality was detected (Fig. 2). The left ventricle appeared to contract well; its peak pressure was 140/0-6 mm Hg and the dP/dT (first derivative of left ventricular function) was 1530 mm Hg/s. The patient was reassured, advised to seek psychiatric help and discharged. Two weeks later she suffered an acute inferior wall infarction and the serum enzyme values increased appropriately. Her early hospital course was complicated by ventricular tachyarrhythmias and hypotension.
Three months later at reassessment the patient continued to complain of atypical angina. A loud fourth heart sound was the only abnormal physical finding. The EGG revealed inferior wall infarction (Fig. 3). Angiography demonstrated hypokinesia of the posterior left ventricular wall but the end-diastolic pressure (6 mm Hg) and the dP/dT (1530 mm Hg/s) were still normal. No abnormality was noted in the coronary arterial tree (Fig. 4). Discussion The cause of angina in this and other cases of syndrome X is unknown. As James1 suggested, it is possible that the coronary arteries are atheromatous but are not identified as such because of unsophisticated angiographic techniques and observer error. However, patients with angina usually have severe atheromatous disease affecting two or more coronary arteries and, although angiographic underestimation of the extent of disease is frequent, it is unlikely that no abnormality would be identified in the presence of severe disease.2 Spasm of the coronary arteries3'4 is a possible cause of angina and infarction but is improbable in this case in view of the normal ECGs during pain and the absence of spasm during angiography.
aVR
FIG. 1-Resting electrocardiogram prior to infarction in patient with syndrome X.
An acute occlusion from embolism might have resulted in infarction, with the artery being recanalized prior to
A 48-year-old nurse was referred for angiography. She had suffered for 5 years from recurrent retrosternal crushing pains, not always precipitated by effort, lasting 1 to 3 minutes and accompanied by diaphoresis and light-headedness. Nitroglycerin did not always relieve the pain but propranolol, 160 mg/d, was of transient benefit. She smoked 10 cigarettes a day. Total hysterectomy had been performed in 1967 and oral estrogens were used sporadically thereafter. She was slim and anxious, with no physical abnormalities. Her blood pressure was 140/70 mm Hg. Postprandial blood glucose and cholesterol values were normal but the value of serum triglycerides was elevated (254 mg/dl). Chest radiograph and resting electrocardiogram (EGG) were normal (Fig. 1), as were several EGGs taken during episodes of pain. Master's two-step stress test produced no symptoms but it did produce ST-segment depression of 1.5 mm on the EGG and Reprint requests to: Dr. D. Kavanagh-Gray, Division of cardiology, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC V6Z 1Y6
FIG.
2-Coronary
anglograms
prior
to
infarction.
Left:
left
coronary
artery.
Right:
angiography. This is the explanation favoured by Arnett and Roberts5 in reviewing 45 ceses of patients with "myocardial infarction and angiographically normal coronary arteries". However, these patients were usually asymptomatic before and after infarction, while my patient was not. Recurrent embolism is an implausible explanation for her repeated episodes of pain. Small-vessel disease has been postulated as the cause of syndrome X.6 Richardson, Livesley and Oram7 performed transvenous endomyocardial biopsy in seven patients with syndrome X and found no evidence of small vessel disease but they did find attenuation of hypertrophied myocardial fibres, a change compatible with that described in congestive cardiomyopathy. Smallvessel disease may occasionally cause I
vi
II
V2
in
V3
aVR
V4
LVL VS aVF
V6
FIG. 3-Electrocardiogram following infarctlon.
syndrome X but it cannot account for all cases. It has been postulated that ischemic symptoms may result from an impairment in oxygen diffusion, and Eliot and Mizukami8 have demonstrated apparent physiochemical abnormalities of hemoglobin in a group of patients with ischemic symptoms. Eliot and Bratt9 have shown, however, a rightward shift of hemoglobin dissociation curves in such patients, and it has been pointed out that such a defect would render oxygen more available. Thus these abnormalities of hemoglobin function are of questionable significance in explaining the symptoms of syndrome X. Inappropriate use of oxygen by the myocardium, resulting in ischemia, is a final possible explanation. Many studies have demonstrated that a proportion of patients with syndrome X have abnormal lactate metabolism under stress, but the cause is unclear.10-13 Neill and Hattenhauer14 noted anginal pain and chemical signs of myocardial hypoxia in patients with coronary artery disease who purposefully hyperventilated, and postulated that hypocapnic alkalosis interfered with myocardial oxygen supply by coronary vasoconstriction and increased oxygen affinity of the blood. Thus, they suggested, hyperventilation may be one cause of the symptoms of syndrome X. This postulate is attractive since it seems that a large proportion of patients with syndrome X are psychoneurotic.10 It seems unlikely, however, that hyperventilation alone could result in myocardial infarction. Whatever the cause - and syndrome
X may represent the clinical manifestation of a variety of conditions - the prognosis is considered to be good. Likoff, Segal and Kasparian55 noted no deterioration in 15 patients with syndrome X who were followed for 1 to 3 years. Bemiller, Pepine and Rogers16 observed 37 patients for a mean of 4.1 years and noted improvement in symptoms in 80% and stability of symptoms in 20%. In none did heart failure or infarction occur; one died suddenly but the cause of death could not be identified at autopsy. Transmural infarction, as in my patient, is unusual in those with syndrome X; however, Kemp and associates10 noted evidence of infarction on EGGs in 4 of 200 such patients, and Eliot and Bratt5 reported that in 3 patients who died a few months after angiography, necropsy revealed normal coronary arteries but subendocardiac infarcts. References 1. JAMES TN: Angina without coronary disease (sic). Circulation 42: 189, 1970 2. PstouDFsT WL, SHIREY EK, SONES FM: Selective cine coronary arteriography. Circulation
33: 901, 1966 3. LEVENE DL, Mmsts MG: Catheter-induced coronary spasm (C). Can Med Assoc 1 111: 647, 1974
4. CHOQUET Y, PROULX J, PRIMEAU R, et al: Coronary hypertonia and angina. Ibid, p 161 5. ARNETI-F EN, ROBERTS WC: Acute myocardial infarction and angiographicaily normal coronary arteries. Circulation 53: 395, 1976 6. JAMES TN: Pathology of small coronary ar-
teries. Am I Cardiol 20: 679, 1967
7. Rsc.nnso. PJ, LsvasLa. B, OasM 5: Angina pectoris with normal coronary arteries. Transvenous myocardial biopsy in diagnosis. Lancet
2: 677, 1974
8. ELIOT RS, MIZUKAMI H: Oxygen affinity of hemoglobin in persons with acute myocardial infarction and in smokers. Circulation 34: 331, 1966
9. ELIOT RS, BRATr 6: The paradox of myocardial ischemia and necrosis in young women with normal coronary arteriograms. Am I
Cardiol 23: 633, 1969
10. KEMP HG, VOKONAS PS, COHN PF, et al: The anginal syndrome associated with normal coronary arteriograms. Am I Med 54: 735. 1973
11. ARBoGAST R, BOURASSA MG: Myocardial function during atrial pacing in patients with angina pectoris and normal coronary arteriograms. Am I Cardiol 32: 257, 1973 12. NEILL WA, KASSEBAUM DG, JUOKINS MP: Myocardial hypoxia as the basis for angina
pectoris in a patient with normal coronary arteriograms. N Engi I Med 279: 789, 1968
13. KEMP HG, ELLIoTr WC, GostuN R: The
anginal syndrome with normal coronary arteriography. Trans Assoc Am Physicians 80: 59, 1967
14. NEILL WA, HATrENHAUER M: Impairment of myocardial 02 supply due to hyperventilation. Circulation 52: 854, 1975 15. LIKOFF W, SEGAL BL, KASPARIAN H: Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engi I Med 276:
12975
1063, 1967
16. BEMn.LER CR, PEPINE CJ, RoGERS AK: Long-
FIG. 4-Coronary angiograms following Infarction. Left: left coronary artery. Right: right coronary artery. 386 CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116
term observations in patients with angina and normal coronary arteriograms. Circulation 47:
36, 1973
Transmural myocardial Infarction occurred In a 48-year-old woman with syndrome X - atypical angina pectorls and anglographically normal coronary arteries. Before the infarction her electrocardiogram had been normal at rest but showed lschemia after exercise. Angiography 3 months after infarction revealed a normal coronary tree but hypokinesla of the posterior left ventricular wall. Un infarctus transmural du myocarde est survenu chez une femme de 48 ans atteinte du syndrome X - une angine de poitrine atypique avec angiographie normale des artores coronalres. Avant l'infarctus Ia patlente avait un 6lectrocardiogramme normal au repos mals presentait des signes d'lsch6mle apr&s effort. Une angiographie pratiquee 3 mois apr.s I'lnfarctus a r6v616 un systeme coronaire normal mais une hypoklnesie de Ia paroi post6rleure du ventricule gauche. Angina pectoris in the presence of angiographically normal coronary arteries - "syndrome X" - is considered to have a good prognosis. In the case reported below a woman with syndrome X suffered a transmural myocardial infarction; a normal coronary tree was demonstrated by angiography before and after the event. Case report
was therefore interpreted as positive for ischemia. Coronary and left ventricular angiography was performed by Judkins' technique under meperkline and secobarbital sedation. Multiple views of both coronary arteries were obtained with both motion and still photography; no abnormality was detected (Fig. 2). The left ventricle appeared to contract well; its peak pressure was 140/0-6 mm Hg and the dP/dT (first derivative of left ventricular function) was 1530 mm Hg/s. The patient was reassured, advised to seek psychiatric help and discharged. Two weeks later she suffered an acute inferior wall infarction and the serum enzyme values increased appropriately. Her early hospital course was complicated by ventricular tachyarrhythmias and hypotension.
Three months later at reassessment the patient continued to complain of atypical angina. A loud fourth heart sound was the only abnormal physical finding. The EGG revealed inferior wall infarction (Fig. 3). Angiography demonstrated hypokinesia of the posterior left ventricular wall but the end-diastolic pressure (6 mm Hg) and the dP/dT (1530 mm Hg/s) were still normal. No abnormality was noted in the coronary arterial tree (Fig. 4). Discussion The cause of angina in this and other cases of syndrome X is unknown. As James1 suggested, it is possible that the coronary arteries are atheromatous but are not identified as such because of unsophisticated angiographic techniques and observer error. However, patients with angina usually have severe atheromatous disease affecting two or more coronary arteries and, although angiographic underestimation of the extent of disease is frequent, it is unlikely that no abnormality would be identified in the presence of severe disease.2 Spasm of the coronary arteries3'4 is a possible cause of angina and infarction but is improbable in this case in view of the normal ECGs during pain and the absence of spasm during angiography.
aVR
FIG. 1-Resting electrocardiogram prior to infarction in patient with syndrome X.
An acute occlusion from embolism might have resulted in infarction, with the artery being recanalized prior to
A 48-year-old nurse was referred for angiography. She had suffered for 5 years from recurrent retrosternal crushing pains, not always precipitated by effort, lasting 1 to 3 minutes and accompanied by diaphoresis and light-headedness. Nitroglycerin did not always relieve the pain but propranolol, 160 mg/d, was of transient benefit. She smoked 10 cigarettes a day. Total hysterectomy had been performed in 1967 and oral estrogens were used sporadically thereafter. She was slim and anxious, with no physical abnormalities. Her blood pressure was 140/70 mm Hg. Postprandial blood glucose and cholesterol values were normal but the value of serum triglycerides was elevated (254 mg/dl). Chest radiograph and resting electrocardiogram (EGG) were normal (Fig. 1), as were several EGGs taken during episodes of pain. Master's two-step stress test produced no symptoms but it did produce ST-segment depression of 1.5 mm on the EGG and Reprint requests to: Dr. D. Kavanagh-Gray, Division of cardiology, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC V6Z 1Y6
FIG.
2-Coronary
anglograms
prior
to
infarction.
Left:
left
coronary
artery.
Right:
angiography. This is the explanation favoured by Arnett and Roberts5 in reviewing 45 ceses of patients with "myocardial infarction and angiographically normal coronary arteries". However, these patients were usually asymptomatic before and after infarction, while my patient was not. Recurrent embolism is an implausible explanation for her repeated episodes of pain. Small-vessel disease has been postulated as the cause of syndrome X.6 Richardson, Livesley and Oram7 performed transvenous endomyocardial biopsy in seven patients with syndrome X and found no evidence of small vessel disease but they did find attenuation of hypertrophied myocardial fibres, a change compatible with that described in congestive cardiomyopathy. Smallvessel disease may occasionally cause I
vi
II
V2
in
V3
aVR
V4
LVL VS aVF
V6
FIG. 3-Electrocardiogram following infarctlon.
syndrome X but it cannot account for all cases. It has been postulated that ischemic symptoms may result from an impairment in oxygen diffusion, and Eliot and Mizukami8 have demonstrated apparent physiochemical abnormalities of hemoglobin in a group of patients with ischemic symptoms. Eliot and Bratt9 have shown, however, a rightward shift of hemoglobin dissociation curves in such patients, and it has been pointed out that such a defect would render oxygen more available. Thus these abnormalities of hemoglobin function are of questionable significance in explaining the symptoms of syndrome X. Inappropriate use of oxygen by the myocardium, resulting in ischemia, is a final possible explanation. Many studies have demonstrated that a proportion of patients with syndrome X have abnormal lactate metabolism under stress, but the cause is unclear.10-13 Neill and Hattenhauer14 noted anginal pain and chemical signs of myocardial hypoxia in patients with coronary artery disease who purposefully hyperventilated, and postulated that hypocapnic alkalosis interfered with myocardial oxygen supply by coronary vasoconstriction and increased oxygen affinity of the blood. Thus, they suggested, hyperventilation may be one cause of the symptoms of syndrome X. This postulate is attractive since it seems that a large proportion of patients with syndrome X are psychoneurotic.10 It seems unlikely, however, that hyperventilation alone could result in myocardial infarction. Whatever the cause - and syndrome
X may represent the clinical manifestation of a variety of conditions - the prognosis is considered to be good. Likoff, Segal and Kasparian55 noted no deterioration in 15 patients with syndrome X who were followed for 1 to 3 years. Bemiller, Pepine and Rogers16 observed 37 patients for a mean of 4.1 years and noted improvement in symptoms in 80% and stability of symptoms in 20%. In none did heart failure or infarction occur; one died suddenly but the cause of death could not be identified at autopsy. Transmural infarction, as in my patient, is unusual in those with syndrome X; however, Kemp and associates10 noted evidence of infarction on EGGs in 4 of 200 such patients, and Eliot and Bratt5 reported that in 3 patients who died a few months after angiography, necropsy revealed normal coronary arteries but subendocardiac infarcts. References 1. JAMES TN: Angina without coronary disease (sic). Circulation 42: 189, 1970 2. PstouDFsT WL, SHIREY EK, SONES FM: Selective cine coronary arteriography. Circulation
33: 901, 1966 3. LEVENE DL, Mmsts MG: Catheter-induced coronary spasm (C). Can Med Assoc 1 111: 647, 1974
4. CHOQUET Y, PROULX J, PRIMEAU R, et al: Coronary hypertonia and angina. Ibid, p 161 5. ARNETI-F EN, ROBERTS WC: Acute myocardial infarction and angiographicaily normal coronary arteries. Circulation 53: 395, 1976 6. JAMES TN: Pathology of small coronary ar-
teries. Am I Cardiol 20: 679, 1967
7. Rsc.nnso. PJ, LsvasLa. B, OasM 5: Angina pectoris with normal coronary arteries. Transvenous myocardial biopsy in diagnosis. Lancet
2: 677, 1974
8. ELIOT RS, MIZUKAMI H: Oxygen affinity of hemoglobin in persons with acute myocardial infarction and in smokers. Circulation 34: 331, 1966
9. ELIOT RS, BRATr 6: The paradox of myocardial ischemia and necrosis in young women with normal coronary arteriograms. Am I
Cardiol 23: 633, 1969
10. KEMP HG, VOKONAS PS, COHN PF, et al: The anginal syndrome associated with normal coronary arteriograms. Am I Med 54: 735. 1973
11. ARBoGAST R, BOURASSA MG: Myocardial function during atrial pacing in patients with angina pectoris and normal coronary arteriograms. Am I Cardiol 32: 257, 1973 12. NEILL WA, KASSEBAUM DG, JUOKINS MP: Myocardial hypoxia as the basis for angina
pectoris in a patient with normal coronary arteriograms. N Engi I Med 279: 789, 1968
13. KEMP HG, ELLIoTr WC, GostuN R: The
anginal syndrome with normal coronary arteriography. Trans Assoc Am Physicians 80: 59, 1967
14. NEILL WA, HATrENHAUER M: Impairment of myocardial 02 supply due to hyperventilation. Circulation 52: 854, 1975 15. LIKOFF W, SEGAL BL, KASPARIAN H: Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engi I Med 276:
12975
1063, 1967
16. BEMn.LER CR, PEPINE CJ, RoGERS AK: Long-
FIG. 4-Coronary angiograms following Infarction. Left: left coronary artery. Right: right coronary artery. 386 CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116
term observations in patients with angina and normal coronary arteriograms. Circulation 47:
36, 1973
