unstable angina pectoris clinical, angiographic, and ... fileunstable angina pectoris, together with...

British Heart Journal, 1976, 38, 257-263.

Unstable angina pectorisClinical, angiographic, and myocardialscintigraphic observations1

Michael S. Donsky, George C. Curry, Robert W. Parkey, Steven L. Meyer,Frederick J. Bonte, Melvin R. Platt, and James T. WillersonFrom the Departments of Internal Medicine (Cardiac Unit), Radiology (Nuclear Medicine) and Surgery(Division of Cardiovascular Surgery) at the University of Texas (Southwestern) Medical School, Dallas,Texas, and Parkland Memorial Hospital, Dallas, Texas, U.S.A.

The clinical, left ventricular and coronary angiographic data, and the technetium-99m stannous pyrophosphate(SSmTc-PYP) myocardial scintigraphic results are presented in 31 patients with unstable angina pectoris.One-third of these patients had positive 99,'Tc-PYP myocardial scintigrams in a pattern suggesting limitedand diffuse subendocardial necrosis. The positive 9smTc-PYP myocardial scintigrams occurred without-diagnostic electrocardiographic and cardiac enzyme changes suggestive of myocardial infarction; positivescintigrams seemed to occur more commonly in patients with continuing pain after admission and in thosewithout previous history of myocardial infarction. The positive 99mTc-PYP myocardial scintigrams did notcorrectly predict coronary anatomical patterns except that positive scintigrams occurred only in patients withcoronary artery disease. Neither did the positive scintigrams necessarily occur in that group of patients withthe poorest ventricular function though the 2 patients with the lowest ejection fractions both had positive99mTc-PYP myocardial scintigrams. Finally, when positive ssmTc-PYP scintigrams are the only evidencesuggestive of limited subendocardial infarction in patients with unstable angina pectoris, they do not appearto have any prognostic significance in terms of longevity or response to pharmacological or surgical therapy,.though the follow-up period so far is short.

Unstable angina pectoris is an expression of ischae- assumed increased importance since the demon-mic heart disease comprising several heterogeneous stration that myocardial infarction is often pre-syndromes intermediate between chronic, stable ceded by premonitory symptoms (Solomon,angina and acute myocardial infarction (Sampson Edwards, and Killip, 1969; Hochberg, 1971;and Eliaser, 1937; Beamish and Storrie, 1960; Nixon and Bethell, 1974). Rapid advances in the-Wood, 1961; Resnik, 1962; Vakil, 1964). Attempts technique of coronary artery revascularization haveto define its natural history have been beset by imn- led to the application of this surgical procedure toprecise and variable diagnostic criteria, differences patients with certain unstable anginal syndromes.in patient populations, and in some instances lack The major objectives in these situations are theof arteriographic confirmation of obstructive coron- prevention of acute myocardial infarction and theary artery disease (Fulton et al., 1972; Krauss, prolongation of life (Lambert et al., 1971; FavaloroHutter, and DeSanctis, 1972; and Gazes et al., et al., 1971; Vogel et al., 1971; Bolooki et al.,1973). Clinical recognition of these syndromes has 1972; Vogel et al., 1975).

A new myocardial scintigraphic technique, using-Received 15 August 1975. technetium-99m stannous pyrophosphate, has re-'This work was supported in part by grants from the Harry S. cently been shown to add another dimension to ourMoss Heart Fund and the Ischemic Heart Disease Specialized ability to recognize acute myocardial infarction inCenter of Research (SCOR). Dr. Willerson is an Established man and in animals (Parkey et al., 1974; WillersonInvestigator of the American Heart Association; Dr. Parkeyis a Scholar in Radiological Research, James Picker Founda- et al., 1975 a, b; Bonte et al., 1974). The applicationtion. of this new imaging technique to 31 patients with

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258 Donsky, Curry, Parkey, Meyer, Bonte, Platt, and Willerson

unstable angina pectoris, together with a descrip- myocardial infarction was established in 12 patients bytion of the clinical, left ventriculographic, and either review of previous records or by the presence ofcoronary arteriographic findings, forms the basis diagnostic Q waves on the electrocardiogram.for this report. All patients had myocardial imaging performed ap-

proximately 60 minutes after the intravenous injectionof 15 mCi of technetium-99m tagged to 5 mg stannous

Methods pyrophosphate (99mTc-PYP). The technical aspects andhistorical background of this imaging process have been

The 31 patients studied were admitted to the coronary reported previously from our institution (Parkey et al.,care unit at Parkland Memorial Hospital, Dallas, Texas. 1974; Willerson et al., 1975 a, b). The majority of theThere were 19 men; the age range was 34 to 68 years myocardial scintigrams were obtained at the patient's(mean 52 years). Unstable angina for the purposes of this bedside using a portable Nuclear Data scintillationstudy was defined as either crescendo angina or acute camera. Scintigrams were generally obtained within 24coronary insufficiency. hours of admission and many of the patients had at least

Acute coronary insufficiency represented that situa- one follow-up scintigram 2 to 4 days after admission.tion in which a single relatively prolonged episode of The imaging was done in at least three views: anterior,chest pain occurred in a patient with a background of left anterior oblique, and left lateral.stable angina pectoris. Eight patients presented with a The myocardial scintigrams were graded on a 0 tohistory of stable angina in the past and one or more 4+ scale according to the degree of uptake of therecent episodes of angina lasting more than 30 minutes, radionuclide over a certain region of the heart, as des-simulating acute myocardial infarction. The presenting cribed previously (Parkey et al., 1974; Willerson et al.,episode of pain was more severe than previous ones and 1975 a, b). A negative scintigram is shown in Fig. 1.was not entirely relieved by nitroglycerin. Acute transmural myocardial infarction presents as an

Twenty-three patients exhibited a crescendo angina intense, localized area of increased activity (3 to 4+)pattern. This was defined as a definite and progressive over the anatomical region of the heart corresponding tochange in the pattern of stable angina without any electrocardiographic localization of the infarct (Fig. 2)demonstrable precipitating cause such as increased (Parkey et al., 1974; Willerson et al., 1975 a, b). Acutephysical activity, emotional stress, or discontinuance of subendocardial infarction, on the other hand, is charac-medical therapy. Specifically, their angina was more terized scintigraphically by faintly positive, diffusefrequent, of longer duration, less responsive to nitro- 99mTc-PYP myocardial uptake (2+) (Fig. 3) which isglycerin, and occurred with less provocation than pre- generally difficult to localize (Willerson et al., 1975 a, b).viously. Cardiac catheterization with selective coronary arterio-The cardiac rhythm was continuously monitored graphy was performed in each of these patients after the

graphically in the coronary care unit. Standard 12-lead completion of the diagnostic studies described above.electrocardiograms and serial serum enzyme deter- These studies were done 3 to 14 days after admissionminations were performed for at least 3 consecutive and after propranolol had been discontinued for at leastdays after hospital admission. Myocardial infarction was 24 hours. Left ventriculography was performed in theconsidered to have been excluded if there were: 1) no right anterior oblique position, and filming was done at 60rise in serum AST or CK above normal values in the frames/s with a 35 mm camera. Left ventricular end-absence of intramuscular injections; 2) no new QRS diastolic and end-systolic volumes were determined byabnormalities on the electrocardiogram; and 3) non- the area length method (Kasser and Kennedy, 1969).specific alterations of the ST segment and T wave that Left ventricular ejection fraction was calculated as thewere of transient nature only. A diagnosis of previous ratio of stroke volume to end-diastolic volume. Coronary

FIG. 1 A negative 99mTc-PYP scintigram. Panel A is an anterior view, panel B a leftanterior oblique view, and panel C a left lateral view. Note the uptake in the sternum andvertebral column (arrows point to these structures in panel A). Also note the faint uptakeof the 99m Tc-PYP in the ribs.



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Unstable angina pectoris 259

m u~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~*FIG. 2 A 99mTc-PYP myocardial scintigram that shows an anterior and apical myocardialinfarction. The three views are the same as in the preceding figure. Note the increaseduptake of the 99mTc-P YP in the anterior and apical regions of the heart.

arteriographic lesions were considered significant if they that observed in patients with acute subendo-produced at least a 70 per cent reduction in luminal cardial infarction (Willerson et al., 1975 a, b).diameter. However, none of these 11 patients exhibited any

Initial treatment in all patients consisted of sub- of the enzymatic or electrocardiographic criterialingual isosorbide dinitrate and oral propranolol indicating the presence of myocardial necrosis.hydrochloride as needed for control and prevention of The clinical features, coronary arteriographicfurther attacks of ischaemic pain. Every attempt was The

and l ventular ctiona ractionremade to relieve the chest pain in these patients before findigs, and left ventricular ejection fractions aresubjecting them to cardiac catheterization and in nearly detailed in Tables 1 and 2. A comparison of*every instance this was successful (see 'Results'). clinical features between these two scintigraphic

groups (Table 3) shows an identical mean age, thatprevious myocardial infarction appeared to be

Results slightly more common in those with negative scinti-

The results of the 99mTc-PYP myocardial imag- grams, and that the crescendo pattern of angina anding in these patients were of interest. Twenty recurrence of angina after the initiation of strictpatients had negative S9mTc..PYP myocardial bed-rest tended to be more characteristic of thosesctientirs (ablnegi). Eleven Pae (Tcabrlea patients with positive scintigrams. Of interest is the(35s rof th entire roup) showed faint and dif fact that all the patients with positive 9smTc-PYPfusely positive uptake of the 9omTcPYP in a 2d+ scintigrams had crescendo angina except for twopositive pattern (Parkey et al., 1974; Willerson who had coronary insufficiency (Tables 1 and 2).et al., 1975 a, b). This pattern (Fig. 4) is similar to Left ventricular function, as determined by the

left ventricular ejection fraction, showed only atendency (not statistically significant) towardsslightly poorer ventricular performance in thosepatients with positive 99mTc-PYP myocardialscintigrams. The 2 patients (patients CO and LJ)with the lowest ejection fractions both had positive99mTc-PYP myocardial scintigrams (Table 2). Twopatients (JM and GW) with positive scintigrams hadventriculographic studies inadequate for volumedeterminations because of ventricular ectopic beatsduring angiography (Table 2).

Coronary arteriography was uneventfully per-formed in all patients; the results are summarizedin Tables 1 and 2. Three patients had angio-graphically normal coronary arteries, an incidence of10 per cent for the entire group. Each of these 3

FIG. 3 A 99mTc-PYP scintigram obtained in a patients had a negative myocardial scintigram.patient with an acute subendocardial myocardial Isolated lesions of single coronary arteries were ob-infarction. Note the characteristic faint and diffuse served in 4 patients, 2 of whom (JM and DD) haduptake of the 99mTc-PYP in this type of infarction. disease localized to circumflex marginal vessels in



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TABLE 1 20 patients with unstable angina pectoris and negative 99mTc-PYP myocardial scintigrams

Previous Clinical Angina EF Sites ofPatient Age and sex MI syndrome in CCU (%) stenosis

LE 49 M 0 CI 0 68 0ES 34 M 0 CI 0 61 0CJ 45 F 0 CA 0 58 0MS 39 F 0 CA + 58 LEJ 46 M + CA 0 52 L, CAR 44F 0 CA 0 65 C, RDP 62M + CA 0 65 LM, L, C, RLR 46F 0 CA 0 64 L, RDO 52 F + CI + 59 L, C, RLC 50 F + CI 0 63 L, C, RDF 66M 0 CA + 47 LM, C, RDW 38M + CI 0 61 L, C, RFC 61 M + CA + 63 L, C, RJV 35 M + CI 0 60 LM, L, C, RFR 51 M + CA 0 45 L, C, RCB 68 F 0 CA 0 65 LM, L, C, RAA 62 F + CA 0 41 L, C, RTH 66M + CA 0 41 L, C, RJB 51 M 0 CA 0 39 LM, L, C, RCAI 58 M 0 CA 0 43 L, C, R

CI, coronary insufficiency; CA, crescendo angina; EF, ejection fraction; L, left anterior descending coronary artery; LM, leftmain coronary artery; C, circumflex coronary artery; R, right coronary artery.

TABLE 2 11 patients with unstable angina pectoris and 2+ positive 99mTc-PYP myocardial scintigrams

Previous Clinical Angina EF Sites ofPatient Age and sex MI syndrome in CCU (%) stenosis

JM 55M 0 CA + * CDD 50F 0 CA + 57 CCO 55 M 0 CA 0 22 L, CLJ 53M + CI 0 26 L, C, RJW 48 M 0 CA 0 45 L, C, RBW 56 M 0 CA + 56 L, C, RSW 51 M 0 CA 0 59 LM, L, REL 61 M 0 CA + 57 LM, L, C, REB 59M + CI 0 39 C, RGW 37 F 0 CA + * LCT 53F 0 CA + 71 L,C,R

Abbreviations as in Table 1.*Accurate measurement impossible because of frequent ventricular premature beats during left ventricular angiography.

association with positive 99mTc-PYP myocardial pain. Whereas pain did recur after admission in 10scintigrams. Triple-vessel involvement was present patients, in only 3 of these was there a poor responsein 19 patients (61%), with 7 showing significant to intensive medical therapy. The short-termstenosis of the left main coronary artery before its follow-up in these patients over an average periodbifurcation into anterior descending and circum- of 6 months includes 18 patients who received onlyflex branches. Apart from the absence of normal medical treatment and subsequently had a total ofcoronary arteriograms in those patients with posi- 6 major ischaemic events: 4 deaths and 2 nonfataltive 99mTC-PYP myocardial scintigrams, there myocardial infarctions. None of these 6 eventswere no differences in the distribution of coronary occurred sooner than 2 weeks after admission; 4arteriographic abnormalities between the two occurred in patients unsuitable for surgical inter-groups of patients. vention because of poor left ventricular function orThe institution of strict bed-rest and the initia- unsuitable distal vessels for bypass grafts, one of

tion of treatment with sublingual isosorbide dini- whom was a patient with a 2+ positive 99mTc-PYPtrate and propranolol hydrochloride were highly myocardial scintigram. Permission for necropsysuccessful in most patients in producing relief of was not obtained in this patient. Surgical revas-



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to patients with unstable angina may have prophy-lactic value. Therefore, these interventions deservecareful, controlled study in the future (Fowler,1971). Myocardial scintigraphy may be of assistancenm such investigations. The observation that 35 percent of our unstable angina patients had positive99mTc-PYP myocardial scintigrams identical tothose seen after acute subendocardial myocardialinfarction raises an obvious question. Had thesepatients already sustained a minor degree of sub-endocardial necrosis undetectable by standarddiagnostic methods or did they have severe ischae-mia which was potentially reversible? Experimentalstudies done at our institution in dogs suggest thatthe 99mTc-PYP is accumulated by irreversiblydamaged myocardial cells (Buja et al., 1975 a, b);it has not been possible so far to show that ischaemicbut non-necrotic cells take up 9smTc-PYP. Thecellular basis for the accumulation of 9smTc-PYPby infarcted myocardium is thought to be the

FIG. 4 A 99mTc-PYP myocardial scintigram ob- labelling of calcium which is deposited in crystallinetained from a patient with unstable angina pectoris. form in and near mitochondria in necrotic cells, butNote the faint and diffuse uptake of the 99mTc-PYP the possibility that polymorphonuclear labelling orin a pattern very similar to that shown in the preceding even that some other mechanism may play a partfigure in which a subendocardial infarction was present. has not yet been excluded (Buja et al., 1975 a, b).

In experimental animals histological examinationcularization was carried out in 13 patients, including of these regions has confirmed the correlation be-5 patients with left main coronary artery lesions and tween myocardial necrosis and increased isotope5 patients with 2+ faintly and diffusely positive uptake (Botvinick et al., 1975; Stokely et al., 1976).*9mTc-PYP myocardial scintigrams. There has The possibility does exist, however, that the faintlybeen one operative death and one perioperative and diffusely positive 99mTc-PYP myocardialinfarct in the surgical group so far. The operative scintigrams obtained in one-third of the patientsdeath occurred in a patient with a negative lsmTc- with unstable angina indicate cells which arePYP scintigram; the perioperative infarct occurred severely ischaemic, but not necessarily destined forin a patient with a positive scintigram preoperative- necrosis. Appropriate follow-up scintigraphic dataly; the patient survived. are not available at this time and it is not possible

to comment on evolutionary changes which mayoccur in the ssmTc-PYP myocardial scintigrams in

Discussion these patients spontaneously or after surgical re-vascularization. Such information might be particu-The various surgical, pharmacological, and larly useful in prospective studies designed to

physiologischaltemichniq dievselop vedf tthnedtea evaluate various surgical and medical interventionsment of ischaemic heart diseaeb thae atltin in unstable angina. It is also possible, of course,degree of sophistication whereby their application that the positive s9mTc-PYP myocardial scinti-

grams are false positives. This seems unlikely to usTABLE 3 Comparison of clinical and certain cardiac since with more than 800 patients studied at ourcatherization features in patients with and without institution using this myocardial imaging techniquepositive 9smTc-PYP scintigrams we have no other sizeable patient group without

myocardial infarction but with positive 99mTc-PYPNegative myocardial Positive myocardial myocardial scintigrams, even though many patientsscintigram (20) scintigram (11) with relatively stable angia pectoris have been

Age (yr) 52 52-5 studied. Previous investigators have convincinglyCrescendo angina 14 (70%) 9 (82%) shown that at necropsy in many patients withPrevious MI 10 (50%) 2 (18%) coronary artery disease, there may be scatteredAngina in CCU 4 (20%) 6 (55%) areas of myocardial necrosis with no corres-Ejection fraction 56% 48%~O ponding electrocardiographic or enzyme evidence



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of myocardial infarction during life (Allison et al., 9mTc-PYP myocardial scintigram is 2+ positive1963; Hudson, 1965; Eliot and Edwards, 1974). in patients with unstable angina who have no electro-Thus, it seems possible that the positive 99mTc-PYP cardiographic or enzymatic evidence of infarction.scintigrams obtained in one-third of our patients On the other hand, we would treat the patient aswith unstable angina pectoris do indeed indicate having a myocardial infarct rather than as unstablelimited areas of subendocardial necrosis unde- angina pectoris, when the 99mTc-PYP myocardialtected by traditional means of diagnostic evalua- scintigram is 3-4+ positive, or there is a scinti-tion, viz. electrocardiograms and enzymes. gram that is positive and becomes negative inThe higher than expected incidence of signi- association with a single prolonged episode of pain

ficant lesions involving the left main coronary artery suggesting infarction, or a positive scintigramin our patients is consistent with some other associated with traditional evidence of myocardialprevious observations (Vogel et al., 1975; Conti infarction.et al., 1973). However, the patients with left main Any conclusions about the specific role of thecoronary artery lesions could not be identified on 99mTc-PYP imaging technique in the long-termthe basis of the 99mTc-PYP myocardial scintigrams management of patients with unstable angina wouldin this study. Also the finding of normal coronary be premature at present. However, it seems prob-arteriograms in 10 per cent of our patients with able that at least some if not all of these patientsunstable angina pectoris is similar to that reported with unstable angina pectoris and 2+ diffusely andin other series (Conti et al., 1973; Alison et al., faintly positive 99mTc-PYP myocardial scintigrams1975; Scanlon et al., 1973; Fischl, Herman, and have already sustained a small area of subendo-Gorlin, 1973). cardial infarction undetectable by less sensitiveThere does appear to be a tendency for patients diagnostic tests. The 99mTc-PYP myocardial

with positive 99mTc-PYP myocardial scintigrams scintigram should be a valuable aid in future in-not to have a previous history of myocardial infarc- vestigations into the natural history of unstabletion but to have a clinical presentation of crescendo angina, and in the evaluation of other diagnosticangina with continuing chest pain after admission, methods that will be developed which are capable ofas compared with those patients with negative detecting very small amounts of myocardialscintigrams. A possible explanation is that these damage. It should also be of help in evaluatingpatients have larger amounts of viable but yet therapeutic measures that are designed to interruptseverely ischaemic myocardium with small islands the progression of unstable angina pectoris to myo-of cell death. cardial infarction.The best treatment for patients with unstable

angina is at present unknown. In some centres these We are grateful to Dr. Max Buja at the University ofpangienas atprensientunknown.Insor meentrgesthese Texas (Southwestern) Medical School for discussionpatients are considered virtual surgical emergencies, and advice.In a recently published large series of unstableangina, 85 per cent of the patients treated with pro-pranolol were notably improved, allowing for a'cooling off' period, followed by semi-elective Referencescoronary artery bypass surgery (Alison et al., 1975). Alison, H. W., Moraski, R. E., Mantle, J. A., Rackley, C. E.,The fact that no myocardial infarctions or deaths and Russell, R. O., Jr. (1975). Coronary anatomy andoccurred within 2 weeks of admission to hospital arteriography in patients with unstable angina pectoris.in our series suggests further that definitive cardiac American Journal of Cardiology, 35, 118.Allison, R. B., Rodriguez, F. L., Higgins, E. A., Jr., Leddy,catheterization and coronary arteriography cam J. P., Abelmann, W. H., Ellis, L. B., and Robbins, S. L.probably be safely postponed for several days after (1963). Clinicopathologic correlations in coronary athero-admission especially in those patients who lose their sclerosis. Four and hundred thirty patients studied with

painwith strict bed-rest and appropriate drug postmortem coronary angiography. Circulation, 27, 170.pain with strict bed-rest and appropriate clrug Beamish, R. E., and Storrie, V. M. (1960). Impendingtreatment. myocardial infarction: recognition and management.The brief follow-up period of both medically and Circulation, 21, 1107.

surgically treated patients in this study suggests Bolooki, H., Vargas, A., Ghahramani, A., Sommer, L. S.,that a 2+ faintly and diffusely positive 99mTc-PYP Orvald, T., and Jude, J. R. (1972). Aortocoronary bypassgraft for preinfarction angina. Chest, 61, 247.scintigram in this setting without other evidence of Bonte, F. J., Parkey, R. W., Graham, K. D., Moore, J., andmyocardial infarction is of no immediate prognostic Stokely, E. M. (1974). A new method for radionuclidevalue. Of the 8 severe ischaemic events, 6 occurred imaging of myocardial infarcts. Radiology, 110, 473.in those patients with negative myocardial scinti_ Botvinick, E., Lappin, H., Townsend, R., Shames, D.,Tyberg, J., and Parmley, W. (1975). Non-invasivegrams. We do not therefore delay either necessary quantitation of myocardial infarction with 99mTc (Sn)cardiac catheterization or cardiac surgery when the pyrophosphate: correlation between creatine phospho-



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