Physiologic responses to epinephrine infusion: The basis for a new stress test for coronary artery disease

Physiologic responses to epinephrine infusion: The basis for a new stress test for coronary artery disease Since many patients with chest pain cannot exercise adequately, an alternative stress would be useful to evaluate coronary reserve. We studled the physiologic responses to epinephrine to assess its potential. We report on 39 patients wlth chest paln. Doses from 0.03 to 0.30 pg/kg/min were administered intravenously. Heart rate increased from 72 * 10 to 86 i 12 bpm (mean rt SD), systolic blood pressure (BP) from 122 + 20 to 158 + 18 mm Hg (increased afterload), and rate-pressure product/100 from 88 & 21 to 133 + 18. Rate-corrected pre-ejection period decreased from 141 -t 23 to 92 + 14 msec and LVET/PEP ratio from 0.41 + 0.1 to 0.24 f 0.05 (increased contractility). Increased afterload and contractility increased myocardial oxygen demand. Simultaneously diastolic time and BP decreased, reducing myocardial blood supply. The endocardlal viability ratio fell from 1.27 + 0.3 to 0.80 rir 0.2. These data suggest that epinephrine infusion would be a useful stress test for coronary disease and are supported by a sensitivlty of 87% and specificity of 100% in 23 patlents with known coronary anatomy. (AM HEART J 105554, 1983.)

Eliot

Schechter,

M.D., Michael

F. Wilson,

M.D., and Yin-Suen

Kong, M.D.

Oklahoma City, Okla.

Stress testing is widely used in the diagnostic and functional evaluation of patients suspected of having coronary artery disease (CAD). Exercise is the most commonly used stress in ambulatory patients while pacing has proved valuable in the catheterixation laboratory, although drugs such as isoprotereno1 have also been employed. To perform a treadmill or bicycle exercise test, it is necessary for the patient to work the legs vigorously and cooperate fully by putting forth a maximum effort. The motion produced by exercise often induces ECG recording artifacts, makes measurement of blood pressure inaccurate, and makes noninvasive cardiovascular recordings such as systolic time intervals, echocardiograms, and nuclear images difficult. Angina is often precipitated by emotion or excitement, a response mediated by sympathetic neurohumoral agents. Levine et al.,’ in 1930, were the first to suggest the use of a bolus of subcutane-

From the Cardiology Section, Department istration Medical Center, and the University Center. *Supported Received accepted

by Medical Research for publication March Nov. 12, 1981.

Reprint requests: Center, Cardiac City, OK 73104.

554

Eliot Schechter, Catheterization

Service 2, 1981;

of Medicine, of Oklahoma

Veterans Health

AdminSciences

of the Veterans Administration. revision received Nov. 5, 1981;

M.D., Veterans Administration Medical Laboratory, 921 N.E. 13 St., Oklahoma

ous epinephrine as a stress test for angina pectoris, but this was not widely accepted because of concern that it was dangerous.2 Our previous experience indicated that the infusion of epinephrine in physiologic doses was safe in patients with cardiac disease,3-5 so we evaluated the physiologic responses to epinephrine infusion as a possible diagnostic test for coronary artery disease. This report describes the responses to epinephrine infusion and their implications for its use as a stress test. METHODS Technique. To perform the epinephrine infusion stress test, a solution with an epinephrine concentration of 4 rg/cc was prepared by mixing 1 cc of 1: 1000 epinephrine in 250 cc normal saline or dextrose. This was infused intravenously at dose rates of 0.03, 0.06, 0.12, 0.18, 0.24, and 0.30 pg/kg/min by means of a calibrated infusion pump (Sage instruments model 350). The infusion was continued for 5 minutes at each dose level with continuous monitoring of the patient’s clinical condition and ECG. A 12-lead ECG was recorded before the infusion, during the first, third, and fifth minutes of each infusion rate, and during the first, third, and fifth minutes after termination of the infusion and each 5 minutes until return to baseline. At the same time the arterial blood pressure was measured in the arm opposite to the infusion with the use of a standard blood pressure cuff. Systolic time intervals were recorded before infusion, during the fifth minute of each infusion rate, and 5 minutes after termination. The test

Volume Number

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Table

Epinephrine

infusion

test for CAD detection

555

I. Responsesto epinephrine infusion Dose

Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Rate pressure product

Control

0.03

0.06

72.3 + 9.78 122 2 19.6

77.9 * 9.32 122 i 18.6

85.7 2 12.0 128 -t 18.9

86.9

77.7 k 10.5

73.5 + 8.56

69.3 zk 8.12

88.3 t 20.7

75.9

105.5 t 22.8

-+ 20.7

0.12

0.18

0.24

0.30

86.9 +- 7.54 130 k 27.7

86.2 f 13.2

20.2

86.2 i 11.5 158 i 18.1

69.2

k 8.65

70.4 + 12.6

66.6 * 7.47

116.4

+ 30.3

134

k 12.0 t

129.6 + 25.8

152

128

k 28.4

70.7 + 11.4

+ 19.9

132.9

+ 17.9

(x10*)

PEP, (msec) PEP/LVET Diastolic time

141 + 22.9

0.40 +- 0.09 0.447 f 0.169

125 2 25.8

115 k 22

0.34 f 0.10

0.30 * 0.10

0.421

k 0.102

0.394

k 0.09

108 t 14.3 0.29 + 0.06

102 + 19.8

0.27 + 0.08 0.397 2 0.087 0.394 f 0.104

97.1 + 17.1

92.4 It 13.7

0.26 f 0.07

0.24 t 0.05

0.415

k 0.115

0.402

k 0.091

(secibeat)

Endocardial viability ratio No. of studies

1.29 f 0.28

1.08 k 0.26

39

39

0.93

2 0.24 39

0.93 k 0.21 32

0.84

t

30

0.21

0.83 + 0.18 23

Data are mean +- 1 standard deviation. PEP = rate-corrected pre-ejection period. PEPKVET = ratio of pre-ejection period to left ventricular Diastolic time was calculated by subtracting the systolic pre-ejection period and left ventricular ejection time from cycle length. Endocardial was calculated by dividing the product of diastolic blood pressure and diastolic time by the product of systolic blood pressure and systolic

was terminated before the maximum dose if the patient developed significant ventricular arrhythmias, ischemic ST changes,or severeischemicchest pain. Equipment for cardiopulmonary resuscitation wasavailable in the testing room. Patient population. The 39 patients reported here were being evalutated for chest pain. They had no clinical evidence of significant valvular abnormalities and none was receiving propranolol. Twenty-three of these 39 patients underwent cardiac catheterization with coronary angiography. Significant coronary artery disease was defined as at least 75% reduction in lumen diameter of at least one of the three major coronary arteries. The patients ranged in agefrom 31 to 63 years, with a median age of 55. Measurements and calculations. The 12-leadECG was interpreted aspositive for myocardial ischemiaif any lead showedat least 1 mm of flat or down-sloping ST depression 0.08 secondafter the J point. None of the patients was receiving digitalis preparations. Pressurework of the left ventricle was estimated from the product of systolic blood pressure (BP) and heart rate.8The systolic time intervals were calculated from the simultaneously recorded ECG, phonocardiogram, and carotid pulse tracings and normalized for heart rate according to the method of Weissler et al6 Corrected pre-ejection period and the ratio of pre-ejection period to left ventricular ejection time (PEP/LVET) were used as measuresof contractility.7 Myocardial blood supply was estimated from the product of diastolic blood pressureand diastolic time. Diastolic time was calculated from the cycle length minus the sum of pre-ejection period and ejection time. Myocardial oxygen demand was estimated from the product of systolic blood pressureand systolic time. The endocardial viability ratio9 wascalculated from theseexternal measurementsof

0.80

+ 0.15 11

ejection viability time.

time. ratio

myocardial oxygen supply and demand as follows: Myocardial blood supply is proportional to diastolic BP X diastolic time. Myocardial oxygen demand is proportional to systolic BP X left ventricular ejection time. Endocardial viability ratio = myocardial blood supply/myocardial oxygen demand, or endocardial viability ratio = (diastolic BP x diastolic time)/(systolic BP X LV ejection time). Oliveros et al.‘O have recently shown good correlation between calculations of endocardial ratio basedon external measurementsand calculations made from direct aortic and left ventricular pressurerecordings. Statistical methods. The values reported in Table I and on the graph for each infusion rate are the meansand one standard deviation of all measurementsmadeat that rate. Table I also showsthe number of individuals whosedata were measuredat each infusion rate. The following definitions were used to evaluate the epinephrine infusion test for the diagnosisof obstructive coronary artery disease.Sensitivity is the percentage of patients with the disease who have a positive test and = true positives/all patients with diseaseX 100.Specificity is the percentage of normal patients who have a negative test and = true negatives/normal subjectsx 100. Accuracy is the percentageof all tests that represent true positives plus true negatives and = true positives + true negatives/all tests x 100. The predictive value of a positive test is the percentagethat are true positives and of a negative test, the percentage that are true negatives. Predictive value of positive test = true positives/all positives x 100. Predictive value of negative test = true negatives/all negatives X 100. Comparison between the groups of patients with and without coronary artery diseaseand positive or negative epinephrine infusion tests was made by meansof a 2 x 2 chi square test. A p value of 0.02 or lesswas considered significant.

April,

Schechter,

556

1001

Pulse

Wilson, and Kong

American

7

!

T

aojT./I

I

60

mean

Rate Pressure Product

-I i’l

beatsimin

L 1 SD

12’ 80 mean

0 Dose

Fig.

I .06

.03 of

I .I8

I .12

Epinephrine

I .24 pgm/

1983

Journal

160

1

I T I T T-- 1.------.-----.-• 1

Heart

I .30

0 .03

.06

Dose

of

.12

.18

I

1 SD

.24

.30

kilo/min

1. Pulse response to epinephrine infusion. Heart

rate in beats/min is indicated on the vertical scalewith the dose of epinephrine on the horizontal scale. Zero representsthe control measurements.The data are given asthe mean + one standard deviation of all patients studied at that dose.

Epinephrine

ugm/kilo/min

Fig. 3. Rate-pressure product responseto epinephrine. The product of heart rate and blood pressure X10’ is indicated on the vertical axis, while the doseof epinephrine is indicated on the horizontal axis. Zero represents the control measurements.The data are given as the mean k one standard deviation of all patients studied at that dose.

180-

BP mm Hg

Y I , I 0 .03 .06 Dose

of

I .12 Epinephrine

mean

I .I8

f 1 SD I .24

I .3O

pgm/kilo/min

2. Blood pressure responseto epinephrine is indicated in mm Hg on the vertical axis and the dose of epinephrine on the horizontal axis. Zero represents the control measurements.The data are given asthe mean * one standard deviation of all patients studied at that dose. Fig.

RESULTS Physiologic responses (Table I). With increasing infusion rate there was a gradual increase in heart rate from 72 -+ 9.78 to 86 -t 11.5 beats/min (Fig. 1) confirming that these were physiologic rather than pharmacologic doses. The diastolic blood pressure

decreased from 78 + 10.5 to 71 + 11.4 mm Hg with

increasing epinephrine doses, while there was a gradual increase in systolic pressure from 122 + 19.6 to a peak of 158 & 18.1 mm Hg and an increase in pulse pressure from 44 to 87 mm Hg (Fig. 2). These changes resulted in a progressive increase in the rate pressure product with increasing doses (Fig. 3). The peak level reached, 133 x lo2 + 17.9, is considerably lower than the levels achieved with maximum treadmill exercise where peak values greater than

200 X lo2 are usual. However, the findings show that epinephrine infusion does produce an increase in the pressure work of the heart and, therefore, of myocardial oxygen consumption. The response of the rate-corrected pre-ejection period to epinephrine infusion is shown in Fig. 4. There was progressive shortening of the corrected pre-ejection period from 141 ? 22.9 to 92 _+ 13.7 with increasing doses, evidence of increased contractility. With increasing doses of epinephrine there was a progressive decrease in the PEP/LVET ratio from 0.40 f 0.09 to 0.24 -t 0.05 (Fig. 5), a finding which Weissler et a1.6 showed correlated with an increase in ejection fraction. These increases in contractility induced by epinephrine resulted in a further increase in myocardial oxygen consumption. The infusion of epinephrine caused a shortening of the diastolic time (Fig. 6) as well as a decrease in diastolic blood pressure which, coupled with the increased myocardial oxygen demand, caused a fall in the endocardial viability ratio from 1.29 & 0.28 to 0.80 t- 0.15 (Fig. 7). CorreIations with coronary anatomy. Of the 23 patients who underwent coronary angiography, 15 had coronary artery disease. In nine patients the epinephrine infusion test was performed on the same hospital admission as the coronary angiogram. The range of intervals between angiography and testing ranged from one to 1311 days with a median of 44 days. The resting ECGs in these patients showed ST depression in one, ST elevation in two, and nonspecific ST-T changes in two. Two of these patients had a true positive test (increase in ST

Volume Number

105 4

Epinephrine

160

infusion test for CAD detection

557

1T

140PEPc 120msec loo0 .03

80-

Dose

Q

mean I I 0 .03

I .08

Dose

of

I .I2 Epinephrine

A 1 SD

1 .18 Mgm/kilo

1 .24

1 .30 /min

Fig. 4. PEP, responseto epinephrine. The pre-ejection

period calculated according to the regressionequations of Weissler et al.6is indicated on the vertical axis, while the doseof epinephrine is plotted on the horizontal axis. Zero representsthe control measurements.The data given are the mean + one standard deviation of all patients studied at that dose.

.12

.18

.24 rgm/kilo/min

.30

Fig. 5. The ratio of pre-ejection period (PEP) to left ventricular ejection time (LVET) in responseto epinephrine is plotted on the vertical axis with the dose of epinephrine on the horizontal axis. Zero indicates the control measurements.This has been shown to correlate with left ventricular ejection fraction,7 a decreasingratio indicating an increasing ejection fraction. The data are given asthe mean f one standard deviation of all patients studied at that dose.

.800

segment deviation from the baseline measurement of greater than 1 mm), two had true negative responses, and one had a false negative response. One patient showed complete right bundle branch block and gave a true positive test. The remainder of the patients had either old myocardial infarctions or normal ECGs. Overall, 13 of these 15 had positive epinephrine infusion tests, evidenced by 1 mm of flat or down-sloping ST segments on the la-lead ECG, a sensitivity of 87 % . The eight patients with normal coronary arteries all had negative tests, a specificity of 100 % . Thus of these 23 epinephrine infusion tests, 13 were true positives and eight were true negatives, for a diagnostic accuracy of 91%. The predictive value of a positive test for coronary artery disease was 100%) while the predictive value of a negative test, for excluding coronary disease, was 80 % . The differences between patients with and without coronary disease was significant with p < 0.001. Although these results are encouraging, the diagnostic value of ECG changes must be accepted with reservation because of the very small number of patients on whom these data are available. Recovery after infusion. The physiologic changes and ST segment deviations resolved in all patients within 15 minutes (mean 9 minutes) after termination of the epinephrine. In no patient were there residual alterations in the ECG or physiologic mea-

.08

of Epinephrine

-

Diastolic Time sooset

Al eat .400-

.300mean I I 0 .03 Dose

I .08 of

I -12 Epinephrine

I .18

i

1 SD I .24

1 .30

wgm/kilo/min

6. Epinephrine-induced changes in diastolic time (calculated as the difference between the cycle length and the sum of the pre-ejection period and left ventricular ejection time) are plotted on the vertical axis with the dose of epinephrine plotted on the horizontal axis. Zero indicates the control measurements.The data represent the mean -+ one standard deviation of all patients studied at that dose. Fig.

surements; no patient required propranolol or nitroglycerin to reverse either symptoms or physiologic changes. Side effects. During testing one patient without coronary disease who was being studied because of ventricular arrhythmias had transient, hemodynamically stable, ventricular tachycardia. Two normal subjects and six patients with coronary disease had

April,

558

Schechter,

Wilson,

and Kong

American

1.60

l-00-

.60-

.60

meanf I I 0 .03 .06 Dose

of

1 SD 1 .12 Epinephrine

1 .16

I .24

I .30

ugm/kiIo/min

Fig. 7. Endocardial viability ratio response to epinephrine. The ratio, calculated by the indirect method of Oliveros et al.,” is plotted on the vertical axis and the infused dose of epinephrine on the horizontal axis. Zero represents the control measurements. The data represent the mean * one standard deviation of the mean of all patients who had measurements at that infusion rate.

PVCs. In two patients these produced bigeminy, making measurement of the systolic time intervals impossible, so the test was terminated, In all other patients the epinephrine infusion was continued until positive ST segment changes occurred or until the maximum dose was reached. Seven patients developed ischemic chest or left arm pain during the infusion. In all except one this was associated with diagnostic ischemic ST segment changes and in none did it require termination of the test before the development of ECG changes or obtainment of the maximum infusion rate. Only four other patients developed symptoms-headache in one, shortness of breath in two, and sharp sticking chest pain in one. In no case did these symptoms require termination of the test. The other patients reported no symptoms. Agitation, tremulousness, or anxiety was not seen. In addition to the 39 patients reported here, we have studied an additional 84 patients (total 123 patients) as part of our previous3-5 or ongoing studies. None of these patients had complications from the epinephrine infusion. DISCUSSION

A study by Saphira and Bron,l’ in which epinephrine secretion rates in humans were measured

1983

Heart Journal

directly, showed the mean resting secretion rate was 0.009 pg/kg/min; with mild stress (venography) it rose to 0.032 pg/kg/min, while the highest value measured during pain was 0.22 Bg/kg/min. The dose ranges used in this study, from 0.03 to 0.30 PgI kg/min, approximate these physiologic secretion rates during mild to moderate stress. Roughgardenlp has shown that heart rate and systolic blood pressure rise before the onset of unprovoked rest angina. Similar changes were induced by epinephrine infusion in this study. Not only are two factors that determine the oxygen demands of the myocardium, pressure work8 and contractility,13 increased by epinephrine infusion, but there is a decrease in diastolic time and a decrease in diastolic blood pressure. The resulting fall in the endocardial viability ratio9 suggests that epinephrine stress may be effective in provoking myocardial ischemia. Our preliminary data provide support for this hypothesis with sensitivity and specificity values that exceed those reported for ECG exercise stress testing.14 However, this must be accepted with caution because of the small number of patients studied. Safety of epinephrine infusion. The use of epinephrine as a stress test for ischemic heart disease was first suggested by Levine et al.’ in 1930. They used a subcutaneous injection of 1000 ccg(approximately 15 pg/kg) to test 11 patients with angina. Positive tests were obtained in 10 subjects while one test was inadequate. Ten young and 10 age-matched control subjects had no positive tests. Katz et a1.,2 using the same dose as Levine et al.,’ tested six patients with angina, six normal subjects, and two patients with other types of cardiac disease. Three of the six angina1 patients had positive tests while none of the others did. One patient reported by Cottrell and Wood,15 a 43-year-old woman with hypertension, sinoatrial block, atypical chest pain, and multiple abdominal surgeries, developed hypotension and bradycardia after an attempted epinephrine test. Although 13 of the 17 patients with angina had positive tests (sensitivity 76 % ) and only one of the 46 patients (with pre-existing severe hypertension) had any reaction, the test fell into disrepute as too risky. Significant differences exist between the test proposed by Levine et al.’ and that which we use. Levine’s dose (1000 pg) was 50 times the maximum dose we used in a 70 kg patient. It was given as a single bolus rather than an intravenous infusion, so the test could not be terminated once symptoms developed. We feel that these problems are prevented by our use of small incremental doses given by intravenous infusion. Small intravenous doses

Volume Number

105 4

(0.05 pg/kg/min) were given by Guttler et all8 to 15 thyroid patients before and after propranolol without complications. Sullivan and GorlirP infused 1.5 to 3.5 pglmin epinephrine (0.02 to 0.05 Icg/kg/min assuming a 70 kg patient) at catheterization in 13 patients without and eight patients with coronary disease without complications. Horn et aL20 in Gorlin’s laboratory infused 1 to 4 bg/min epinephrine (0.01 to 0.06 pg/kg/min in a 70 kg patient) to 16 patients with coronary artery disease and two patients with normal coronaries. Again there were no complications. Thus in 54 recorded patients from other laboratories, including 24 with proved coronary artery disease, there have been no complications from the epinephrine infusion. Comparison with exercise stress. Although exercise stress testing has stood the test of time as a screening test for obstructive coronary artery disease, it has several significant drawbacks. The patient must be able to perform vigorous leg exercise and cooperate fully to reach a symptom-limited maximum. The motion of the exercise makes it difficult to record an artifact-free ECG and makes blood pressure measurements inaccurate. Noninvasive studies such as systolic time intervals and echocardiograms cannot be carried out during exercise. Nuclear studies such as myocardial perfusion imaging and gated bloodpool ventriculography require the subject to maintain maximum exercise for one or more minutes after the tracer is injected16 or while imaging is being done17 imposing additional problems. The epinephrine infusion test eliminates these disadvantages. It is easy to obtain an artifact-free ECG and accurately perform noninvasive studies such as pulse and phonocardiographic recordings, echocardiograms, and gated myocardial blood pool scans during epinephrine stress. The fact that the patient need not have the ability or willingness to exercise allows the test to be used in patients who are unable to exercise because of neurologic defects, peripheral vascular disease, obstructive lung disease, or simply fear of pushing themselves. Inadequate tests. Only one test (2.6%) had to be stopped because of ventricular tachycardia. That occurred in a patient who was being studied because of recurrent ventricular tachycardia. At catheterization he had no evidence of organic heart disease. Two other tests were terminated because bigeminy made interpretation of the systolic time intervals, which were part of this research study, impossible. For clinical purposes these patients were hemodynamically stable and it would have been possible to continue the test and evaluate the ST segment

Epinephrine

infusion test for CAD detection

559

changes in the sinus beats. It appears that few “inadequate” tests will occur, a further advantage over treadmill exercise where many patients stop before their maximum heart rate or a positive result is attained. Clinical Smplications. Epinephrine infusion may be considered an acceptable alternative to exercise stress testing for identifying patients with coronary artery disease. It has the advantage that the ability to exercise is not required and, thus, patients with pulmonary disease, neurologic defects, peripheral vascular disease, or other problems precluding exercise can be tested. The patient’s cooperation is not required to achieve an adequate test. Other measurements such as systolic time intervals, echocardiograms, and nuclear ventriculograms are easily performed since the patient is lying quietly during the test. The equipment required, a calibrated infusion pump and ECG machine, are relatively inexpensive. We gratefully acknowledge the assistance of Paula A. Logan and Bong Hee Kim Sung in performing systolic time intervals and epinephrine infusion tests, and Eunice James, Iva Lou Gibson, Fara Jordon, and Ellen Mahoney in typing the manuscript. REFERENCES

1. Levine SA, Ernstene AC, Jacobson EM: The use of epinephrine as a diagnostic test for angina pectoris. Arch Int Med 45:191, 1930. 2. Katz LN, Hamburger WW, Lev M: The diagnostic value of epinephrine in angina pectoris. AM HEART J 7:371, 1932. 3. Salzman SH, Wolfson S, Jackson B, Schechter E: Systolic time intervals in normals and idiopathic hypertrophic subaortic stenosis. Ann Intern Med 72:783, 1970. 4. Salzman SH, Wolfson S, Jackson B, Schechter E: Epinephrine infusion in man; standardization, normal response and abnormal response in idiopathic hypertrophic subaortic stenosis. Circulation 43:137, 1971. 5. Salzman SH, Wolfson S, Schechter E: Epinephrine infusion in left heart failure. Circulation 41-42(suppl 111):195, 1970. 6. Weissler AM, Harris WS, Schoenfeld CD: Systolic time intervals in heart failure in man. Circulation 37:149, 1968. 7. Garrad CL Jr, Weissler AM, Dodge HT: The relationship of alterations in systolic time intervals to ejection fraction in patients with cardiac disease. Circulation 42:455, 1970. 8. Robinson BF: Relationship of heart rate and systolic blood pressure to onset of pain in angina pectoris. Circulation 35:1073, 1967. 9. Hoffman JIE, Buckberg GD: The myocardial supply-demand ratio: A critical review. Am J Cardiol 41:327, 1978. 10. Oliveros RA, Boucher CA, Haycraft GL, Beckmann CH: Myocardial oxygen supply-demand ratio, a validation of peripherally vs centrally determined values. Chest 75:693, 1979. 11. Saphira JD, Bron K: Human epinephrine secretion: Direct measurement of secretion of epinephrine from the human adrenal medulla. J Clin Endocrinol 38:436, 1971. 12. Roughgarden JW: Circulatory changes associated with spontaneous angina pectoris. Am J Med 41:947, 1966. 13. Sonnenblick EH, Skelton CL: Myocardial energetics: Basic principles and clinical implications. N Engl J Med 286:668, 1971. 14. Borer JS, Brensike JF, Redwood DR, Itscoitz SB, Passamani

April,

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Wilson,

and Kong

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ER, Stone NJ, Richardsion SM, Levy RI, Epstein SE: Limitations of the electrocardiogram in predicting coronary artery disease. N Engl J Med 293:367, 1975. 15. Cottrell JE, Wood FC: The effect of epinephrine in angina pectoris. Am J Med Sci 181:36, 1931. 16. Ritchie JL. Trobaueh- GB. , Hamilton GW: Mvocardial imaaing with Thallium-201 at rest and during exercise: Cornpar;son with coronary arteriography and resting and stress electrocardiography. Circulation 56:66, 1977. 17. Borer JS, Bacharach SL, Green MV, Kent KM, Epstein SE, Johnston GS: Real-time radionuclide tine-angiography in the non-invasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary artery disease. N Engl J Med 296:839, 1977.

Heart

1983

Journal

18. Guttler RB, Croxson MS, DeQuarttro VL, Warren DW, Otis CL, Nicoloff ST: Effects of thyroid hormone on plasma adenosine 3’, 5’-monophosphate production in man. Metabolism 26:1155, 1977. 19. Sullivan JM, Gorlin R: Effect of L-epinephrine on the coronary circulation in human subjects with and without coronary artery disease. Circ Res 21:919, 1967. 20. Horn HH, Teichholz LE, Cohn PF, Herman MV, Gorlin R: Augmentation of left ventricular contraction pattern in coronary artery disease by an inotropic catecholamine. Circulation 49:1003, 1974.

A comparison of coronary and internal mammary arteries and i at&m of the results in the etiology of arterbsclerosis Comparison was made between the intimal thickening of the anterior descending branch of the left coronary artery and the internal mammary artery in 352 necropsy examinations. The coronary arteries showed severe intimal thickening, progressing in severity throughout life, whereas the internal mammary showed no more than slight changes at any age. These observations, together with the variation in severity of the changes in different portions of the same vessel, and the freedom from this disease of the smaller arteries throughout the body, strongly suggest that a local or anatomic factor is the dominant tnfluence in coronary artery disease. (AM HEART J 105:560, 1983.)

Frank H. Sims, M.B., Ch.B., Ph.D. Auckland,

New Zealand

Arteriosclerosis continues to be a lively subject of debate,‘e5 and new advances are being constantly reviewed.6-‘4 Fundamental issues are whether factors associated with the homogeneous circulating blood, such as generalized endothelial damage, lipids, platelets, hormones, antibodies, or toxins, can explain the features of arteriosclerosis in view of the specific anatomic distribution of the lesions,15-20 and the observation that certain vessels may carry blood for a whole lifetime without showing significant arterial disease. Any valid theory of arteriosclerosis

From School.

Pathology

Department,

Received accepted

for publication Nov. 16, 1981.

Aug.

*Reprint Auckland,

requests: Private

560

the

University

31, 1981;

Pathology Department, Bag, Auckland. New

revision Medical Zealand.

of

Auckland

received School,

Medical

Nov.

10, 1981;

University

of

must explain the freedom of these vessels from disease as well as the lesions in the affected arteries. Also to he explained is the development of irregular intimal thickening or plaques, a constant feature of advanced lesions in humans. In the investigation recorded here, the coronary and internal mammary arteries in 352 patients of all ages were compared. The internal mammary was chosen for the comparison because it is a systemic vessel of comparable size, situated in the thorax, and subject to the same intrathoracic respiratory pressure changes as the coronary vessels; it is surrounded by similar loose fibrofatty tissue, the lympathic drainage of which differs from that of the heart. Experience has shown that it rarely shows evidence of arterial disease. The results support the conclusion that local or anatomic factors are dominant in the etiology of coronary artery disease.