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Coronary insufficiency in man
Clinical Studies Coronary Physiologic
Insufficiency
in Man
and Electrocardiographic
Correlation*
RICHARD J. WAGMAN, M.D.,HERBERT J.LEVINE,M.D.,JOSEPH V. MESSER, M.D., WILLIAM A. NEILL,M.D.,NORMAN KRASNOW, M.D. and RICHARD GORLIN, M.D., F.A.C.C. Boston,
M
Massachusetts
whenever YOCARDIAL ISCHEMl.4 occurs there exists a discrepancy between the available oxygen supply and the work requirements of the heart muscle. This can be due to narrowing of coronary arteries by occlusive disease or to a decrease in the oxygen-carrying capacity of the blood, as in anemia, or when tissue utilization is blocked, as by cyanide. It may also be due to a relative insufficiency of the arterial tree, as seen in myocardial hypertrophy or when the myocardial energy requirements exceed the maximal flow capacity of the coronary vascular bed. It has long been known that ischemia is associated with electrocardiographic changes. Bayley’s work1 on the evolution of the classic ischemic electrocardiographic pattern in the dog is perhaps the most well known. Only a few attempts have been made, however, to correlate the degree of “coronary insufficiency” with the development of electrocardiographic changes. Wegria2 in 1949 studied this problem by altering directly measured coronary flow in the dog by means of an adjustable clamp. A reduction of coronary flow to 65 to 90 per cent of control values did not generally affect the electrocardiogram, while a reduction of from 30 to 65 per cent produced “slight” changes and a reduction to 30 per cent or less of control flow always produced “marked” changes. Kimura et a1.,3 with similar technics, demonstrated depression of the S-T segment on reduction of coronary flow to one-third the “normal” resting value. Evaluation of myo-
cardial hypoxia was not made in these investigations. Intracellular oxygen tension is equal to or less than the effluent venous oxygen tension. Thus, analysis of venous oxygen tension or saturation can give some idea of at least the highest value within the cell. In the case of the heart, therefore, coronary venous oxygen saturation (allowing for pH) reflects average left ventricular myocardial oxygen tension. It is the purpose of this paper to analyze the relationship, if any, between coronary venous oxygen saturation and the electrocardiographic patterns recorded in a large group of patients. MATERIALS AND METHODS One hundred and fourteen patients have been studied by the technic of coronary venous and systemic arterial catheterization. Coronary blood flow was determined by the nitrous oxide techni@; coronary arteriovenous oxygen differences were determined by the method of van Slyke and Neill.5 Observations were made in the resting state in all. Sixty-eight patients were examined during both rest and a 6 to 8 minute period of supine leg exercise sufficient to raise total body oxygen consumption two to three times the resting level. Multiple coronary venous oxygen saturations were determined before, at various times during, and again following effort. All patients had electrocardiograms taken at rest; all who underwent coronary flow studies during exercise had standard exercise electrocardiograms (Master two-step tests). Because of the correlation between their electrocardiographic findings and long-term follow-up study of patients, we have elected to use the criteria of Mattingly et al.‘**-nonjunctional S-T
* From the Medical Clinics of Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts. This work was supported by grants from the U. S. Public Health Service (N.I.H. H-2637) and the Massachusetts Heart Association (No. 390). MARCH
1962
439
Wagman
440
et al.
36 t
.-E
z
5 ‘0
0-l
El
m30 =‘
‘.
YCORONARY
0
/INSUFFICIENCY \
: z 3
I’
\ \
? : 0 : 0
/ ‘\.
24REST PRE- EXERCISE
I I
\
\
I
I
3
5
EXERCISE
\r
t 7
(Min.)
REST POST- EXERCISE
venous oxygen saturation during exercise. The 1. Change in coronary normal group shows remarkable constancy of the coronary venous oxygen saturation. In those with coronary insufficiency, it fell to a low of 23 per cent below control levels on exercise (p < .005). FIG.
segment depression of 0.5 mm. or more-as our only Patients were lurther evidence of abnormality. classified and analyzed according to whether they were receiving digitalis. RESULTS
For the purposes of this study we have classified our patients with coronary flow studies into three broad categories as follows : normal, abnormal and equivocal. Since it has been shown previously9 that coronary hemodynamics in the presence of diffuse coronary disease may be within normal limits at rest, only those patients who were stressed have been classified into these groups. The normal group had an average of 40 per cent increase in coronary blood flow with exercise (- 8 to +162 per cent), as compared with 34 per cent in the abnormal group (- 5 to +141 per cent). Also demonstrated was a 30 per cent decrease in diastolic vascular resistance (as a measure of coronary vasodilatation) in the normal group (+8 to -82 per cent) and a fall in the “coronary” group of 21 per cent (+14 to - 62 per Coronary arteriovenous oxygen differcent). ence showed no consistent pattern in the normal group (+lO to -23 per cent) but widened 8 per cent (+4 to +12.8 per cent) in the group with coronary arterial disease. The myocardial
oxygen extraction coefficient (A-Vol/AO* was essentially unchanged (-3 per cent relative to resting level) in the normal group, but increased considerably (+12 per cent relative to resting value) in 83 per cent of the coronary In the normal group patients (p < .005). coronary venous oxygen saturation was remarkably constant (Fig. l), but decreased in 83 per cent of the patients with coronary disease. The fall was 23 per cent below control levels in twenty-one of the twenty-nine cases (an absolute decrease in saturation of 5 per cent or more) (p <.005). This latter finding was the one of most importance for this study in defining physiologic coronary insufficiency. One patient could not be clearly classified on the basis of the previously mentioned criteria and was, therefore, considered to be “equivocal.” Correlation
of
Coronary
Hemodynamics
and
Exer-
*This coefficient reflects the amount of oxygen removed per milliliter of arterial blood presented to the A decrease in the coefficient indicates myocardium. less removal and more blood flow in relation to demand; conversely, an increase indicates more oxygen removal and relatively less blood flow in relation to demand. If exercise produced an absolute fall in coronary venous oxygen saturation of 5 per cent or greater or an absolute increase of myocardial oxygen extraction percentage of 3 per cent or greater, this was considered abnormal.i3 THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Coronary
Insufficiency
441
TABLE I Correlation
TABLE II Correlation of the Master Exercise Test with Coronary Physiology in the Undigitalized Patient
of the Master Exercise Test with Coronary Physiology Exercise
Hemodynamics
No. Patients
Electrocardiogram
Normal
Hemodynamics
Abnormal
Equivo-
11 22
1 1
Normal Abnormal Equivocal
2
Total
Normal Abnormal Equivocal
37 30 1
25 7 1
...
Total
68
33
33
with
15
Angina
/\.
.
1962
21 15 1
16 5 1
5 10 .
37
22
15
on Digitalis
/
8
biARCH
Abnormal
Pectoris
Abnormal Correlation
Normal
ma1 hemodynamics had an abnormal tracing. If one eliminates those patients receiving digitalis, there appears to be an even better correlation between the exercise electrocardiogram and hemodynamic evaluation of coronary physiology (Table II). Of this group of thirty-seven patients, twenty-one had flow studies within normal limits; i.e., flow was adequate to oxygen needs and coronary venous saturation was unchanged. Sixteen oxygen of these twenty-one (76 per cent) had normal Master exercise tests. Of the fifteen patients with abnormal flow studies, ten had abnormal exercise electrocardiograms. One patient had equivocal flow studies, with a normal exercise test. A total of twenty-nine patients had definite angina pectoris. Of these, twenty-six had exercise electrocardiograms in addition to coronary flow studies. Twenty of these twenty-six had abnormal coronary hemodynamics (Fig. Fifteen of the twenty-six were not receiving 2).
9 *bnorma1/<\
FIG. 2.
Exercise Electrocardiogram
Patients
Cd
Table I shows the corcise Electrocardiograms: relation between the Master test and the coroTwennary circulation in sixty-eight patients. ty-five of thirty-seven patients with normal hemodynamics had normal exercise electrowhile eleven were abnormal. cardiograms, Twenty-two of thirty patients with abnormal hemodynamics had abnormal exercise tolerance seven were within normal limits. As tests; previously noted, however, digitalis can affect the exercise electrocardiogram with the production of S-T segment depressions, making interpretation either difficult or impossible.‘0 Nevertheless, it is to be noted that if the exercise electrocardiogram remained within normal limits despite digitalization, 76 per cent (twenty-five of thirty-three patients) had normal hemodyAlso, despite the influence of digitalis namics. on the exercise electrocardiogram in the remaining patients, 73 per cent of those with abnormal hemodynamics had an abnormal electrocardiogram while only 30 per cent of those with nor-
Of 26 Patients
No.
20 Hemodynamics
between angina pectoris, exercise test and coronary physiology.
Wagman
442 S-T
20 or <
21 to 25
SEGMENT
26 to 30
DEPRESSION
31 to 35
Coronary
36 to 40 Venous
et al. NORMAL
11
Oxygen
SEGMENT
r
20 or <
41 or >
S-T
21 to 25
26 to 30
Saturation
31 to 35
36 to 40
oh
FIG. 3. Relation of S-T segment to coronary UP~DUSoxygen saturation. Fifty-eight patients of a group of 114 had S-T segment depression at rest. Twenty-five of these (43 per cent) had coronary venous oxygen saturations of less than 26 per cent. Of the fifty-six with normal S-T segments at rest, eleven (20 per cent) had coronary venous oxygen saturations of less than 26 per cent (p < .02).
and nine of these fifteen (60 per cent) had abnormal exercise electrocardiograms. Of this group of nine with both clinical angina pectoris and an abnormal exercise electrocardiohad abnormal eight (89 per cent) gram, flow studies as well. Correlation of Coronury Hemodynamics and Electrocardiograms at Rest: Those patients studied only at rest were grouped initially into two categories: those with and those without S-T The groups segment depression in any lead. were further subdivided according to whether These the patient was receiving digitalis. electrocardiographic changes were then compared with the coronary venous oxygen satuNo attempt was made to corration alone. relate the resting electrocardiogram with the level of coronary flow because even in the presence of coronary arterial disease, this may be within normal limits at rest (uide infru). Figure 3 illustrates the relationship in the resting subject between the electrocardiogram and the coronary venous oxygen saturation (an index of over-all myocardial oxygenation). Fifty-eight patients of a group of 114 had an abnormal electrocardiogram at rest as characterized by persistent depression of the S-T segment on any lead. Twenty-five of these (43 per cent) had coronary venous oxygen By consaturations of less than 26 per cent. trast, of fifty-six patients with normal electro-
digitalis,
cardiograms at rest, eleven (20 per cent) had coronary venous oxygen saturations of less than 26 per cent. Thus, those patients \rith S-T segment depression had lower coronary venous oxygen saturations slightly more often than did those with normal electrocardiograms. This difference is statistically significant (p However, coronary venous oxygen < .02). saturation is decreased as part of the vasoconstrictor response to low output congestive heart failure or mitral stenosis.” Also, it is in these latter conditions that digitalis is used most frequently with its attendant effects on Thus, the correlation the electrocardiogram. be fortuitous. However, the average may coronary venous oxygen saturation was 28.7 per cent with little variation between groups (Table III). For the individual patient, it was impossible to predict the coronary venous oxygen saturation from the electrocardiogram and vice versa. Right-Sided Cardiac Lesions: Of the sixty--eight abpatients studied, sixteen had circulatory normalities affecting primarily the right side of the heart. They presented no evidence of coronary arterial disease, aortic valvular disor hypertension. The lesions in the ease right side of the heart ranged from pure mitral stenosis to pulmonic stenosis to pentalogy of Fallot. These patients, in addition to the routine studies, had right chest leads recorded THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Coronary TABLE
S-T
Segment
Insufficiency elevated
III
Depression at Rest Versus 0 xygen Saturation
Coronary
Venous
exercise In
(‘Z)
IS-T segment depression 42 on digitalis 16 off digitalis Average saturation Normal S-T segment 8 on digitalis 48 off digitalis Average saturation Total average saturation
in only
one
and
failed
to rise with
in the other patients. a
group
of
forty-seven
patients
with
predominant “right-sided lesions” studied at St. Thomas’ Hospital, London by Hood and Daley,‘* only seven had abnormal results of the right precordial lead Master tests. In this
O? Saturation
Segment
443
23.2 28.2 26.8
series also, no correlation tween an abnormal right
28.2 31.2 30.7 28.7
level of right ventricular pressure or both. No studies were performed.
ter
test,
the
presence
could be found beprecordial lead Mas-
of clinical
angina,
the
or pulmonary arterial coronary blood flow
COMMENTS Electrocardiographic abnormalities considered to be representative of myocardial ischemia could not be specifically correlated with decreased coronary venous oxygen saturation per se. This is not surprising. First, it must be appreciated that coronary venous blood comes from areas which may be unevenly perfused in relation to need, particularly with coronary disease. Ischemic areas of functioning muscle, by extracting more oxygen than surrounding areas, will tend to lower coronary venous oxygen content. Areas of scarring usually have a miniscule blood supply. It has been suggested, however, that on occasion large enough blood vessels may traverse these scars to act as small arteriovenous shunts, tending to raise coronary venous oxygen content. Coronary venous oxygen saturation undoubtedly represents the over-all resultant of
as part of their standard Master exercise test. From this group, patients with S-T segment depression of 0.5 mm. or more in any right precordial lead were separated in an attempt to relate an abnormal response to a possible common hemodynamic factor. Four patients had abnormal results from the right precordial lead exercise tolerance test. One of these, a patient with severe mitral insufficiency and pulmonary hypertension, had depression of S-T segments in leads over both left and right precordium (Table IV). The abnormality electrocardiographic could not be correlated with the presence or absence of angina, or with abnormal coronary flow studies. Furthermore, although all patients had elevated right ventricular pressures (in the range of 100 mm. Hg), pulmonary arterial pressure was
TABLE Positive
Right
-
Patirrrt
IV
Precordial
Lead
T Diagnosis
Exercise
Test
Pressure
Angina
Hemodynamic Pattern
Right Ventricle
_ MR hl.1 EL HR”
Pentalogy of Fallot Pulmonic stenosis Tetralogy of Fallot Mitral insufficiencyt; pertension
* Abnormal t Rheumatic MARCH
1962
right- and left-sided heart disease.
precordial
hy-
lead
Normal Abnormal Normal Normal
Yes No Yes
exercise
test.
100/3 135/o 110/o 98/l 1
Hg)
Pulmonary Artery (mean) ___ Rest
? pulmonary
(mm.
7 8 7 64
Exercise
12 8 11 90
444
Wagman
these opposing effects. While sampling at multiple points along the great cardiac vein in various types of heart disease has shown remarkable uniformity of oxygen content,r3 regional changes may be undetected by coronary venous sampling. This is due to the following factors: (1) the ischemic contribution may be very small relative to the total left ventricular coronary flow ; and (2) increases through functioning shunts may occur to counterbalance a decrease in oxygen saturation of blood from an ischemic region. Hence, any measurable abnormality should be regarded as reflecting the end result of a diffuse arterial disease process. It can be calculated that due to the flow-extraction ratio of the myocardium for oxygen, a 10 per cent increase in arteriovenous oxygen extraction is roughly equivalent to a 12 per cent insufficiency of over-all coronary flow, with the implicit understanding that given areas may receive totally different degrees of perfusion. Conversely, it is well known that numerous drugs, changes in osmotic pressure, pH, hyperventilation, ionic imbalance and certain heavy metals can cause S-T segment depression in the electrocardiogram without necessarily producing myocardial hypoxia.14-20 Digitalis, for example, is one of the commonest causes of a depression of the S-T segment. This may be seen as early as 10 minutes following an intravenous injection of digitoxin.” In the case of the whole leaf, this may last as long as 2 to 3 weeks.= Even after complete disappearance of digitalis-induced S-T segment depression, doses of digitalis which would have been completely without effect alone, now cause this change to reappear.% The etiology of these electrocardiographic changes is unknown. The drug affects the monophasic action potential of the ventricle, the T wave, RS-T segment and the duration of the Q-T interval.24 In animals large doses of digitalis have produced myocardial necroses in the subendocardial layers of the left ventricle.25 However, the doses of digitalis required have been in the toxic range. Other factors such as loss of potassium by the heart muscle celP or a change in myocardial metabolism to anaerobic pathway? have been postulated as possible causes of the electrocardiographic changes. Interestingly enough, dehydrocholic acid (Decholin@) causes S-T segment depression also, and it has been suggested that this is due to its structural similarity to the digitalis drugs.28 The explanation for the specific effect which digitalis has on exercise
et al. electrocardiograms is even less clear. As shown by Bing et al., 2g digitalization has no effect on coronary blood flow, degree of coronary vasodilation, coronary venous oxygen saturation or oxygen consumption of the left ventricle. While electrocardiographic and coronary venous oxygen abnormalities showed random variation at rest, changes in these parameters on exercise went hand in hand. Although there was a suggestive relationship within the total group, the correlation became even better if the digitalized patients were excluded. The coincidence between a falling coronary venous oxygen saturation on exercise and an abnormal Master exercise test should not, however, imply that the former is necessarily a cau.ce of the latter, but rather that both phenomena may reflect a common background, i.e., a diffuse occlusive arterial disease process. Sayen et a1.,30 using the polarographic oxygen electrode, showed that following the experimental occlusion of a coronary artery there is a rapid fall in myocardial oxygen tension. Electrocardiographic changes, however, rarely appeared before the period of rapid oxygen change was at least half over, and continued even after the myocardial oxygen tension reached stable levels in the range of less than 25 per cent of control values in the central area of ischemia, and 25 to 75 per cent in the adjacent tissue zones. What additional mechanisms are operative here is uncertain, but alterations in the characteristics of the myocardial cell membrane, potassium or other ionic shifts, glycolysis, or a have been combination of such processes postulated to explain the electrocardiographic changes.30-32 Mechanisms of Angina Pectoris: Even more difficult to explain, and not at all clarified by is the nature of the underlying our data, mechanism producing clinical angina pectoris. Although increased plasma concentrations of norepinephrine and epinephrine have been reported in patients with myocardial infarction and angina pectoris on effort,3s,34 as seen in Table v, in a small group, there was no significant difference between the controls and those patients with clinical angina. Likewise, excess lactate production as evidence of anaerobic glycolysis was demonstrated in only two patients of this seriesi Myocardial serum potassium studies have been inconclusive thus far. Not only need there be no specific correlation between degree of heart damage (as seen in the pathologic specimen) and the development of THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Coronary TABLE v Blood
Catechols
in Patients With Pectoris
Subject
Controls (10 patients) Rest Exercise Angina Pectoris (7 patients) Rest Exercise
and Without
Epinephrine (pg./L.)
Angina
Norepinephrine (rg./L.)
0.8 0.6
2.4 2.5
0.5 0.3
2.5 2.9
but also between physiologic coronary inadequacy as measured by our technics and the development of pain. Furthermore, there is no necessary relationship between the development of electrocardiographic changes following exercise and the presence of clinical angina pectoris. Rumba11 and Acheson, in a study of 660 apparently healthy patients without clinical evidence for coronary or other forms of heart disease, showed that 45 (6.8 per cent) had nonjunctional S-T segment depression in their exercise electrocardiograms. This was noted primarily in patients over the age of 40. One might wonder whether or not, even in the absence of clinical pain, these subjects did indeed have an underlying functional inadequacy of the coronary circulation. Conversely, it would be interesting to determine if the prognosis is better in angina1 patients with a normal exercise electrocardiogram or exercise coronary hemodynamics or both than in those with frank abnormalities. It is interesting that angina pectoris occurs primarily in the “well-functioning” heart and tends to disappear with the onset of heart failure. Thus, it is likely that pain may originate from patchy areas of ischemic myocardium. Although the presence of such patchy ischemic areas may be undetected by the currently employed stress test, it is interesting to speculate on the possible role of such regions in the production of clinical angina pectoris. In response to stress (which drives the “whole heart”) as cardiac tension development increases, the ischemic area may “fall behind” in coronary flow and oxygen consumption. The stage is thus set for pain, but the over-all measured cardiac function is unaffected and may not be detected by our relatively crude “averaging” methods for coronary venous angina,s5
MARCH 1962
Insufficiency
445
oxygen saturations or the cruder coronary flow methods (nitrous oxide). Right-Sided Angina: The concept of rightsided angina is not new. Posselt,37 in one of the earliest statements on the subject, thought that the angina1 pain in a patient with mitral stenosis may have been due to distension of the pulmonary arteries, caused by pulmonary arteriolar spasm. White,38 in 1936, found that angina was rare in the presence of mitral stenosis except in the older age group in which there might be a superimposed coronary atherosclerosis. In 1942 Burgess and Ellis89 concluded that the pain originated from the myocardium was due to a relative anoxia and was associated with a decreased cardiac output which in turn caused impairment of coronary blood flo~.~~ All of their patients had right ventricular hypertrophy. No changes were noted in the limb leads of the electrocardiogram during attacks. Viar and Harrison40 in 1952 revived the concept of pain secondary to distension of the pulmonary artery itself, as in migraine, in a study of six patients with pulmonary hypertension and pain in the chest. They did not rule out coronary insufficiency of the right ventricle, but suggested that failure of the pain to respond to nitroglycerin was against this mechanism, although the drug, among other actions, does lower pulmonary arterial mean pressure.41 No exercise electrocardiogram or catheter studies were presented. Howarth and Lowe42 in 1953 reported the case of a patient with primary pulmonary hypertension with effort syncope, and showed the development of ischemic S-T segment depression in lead Vi on exercise. Stuckeyh3 in an excellent review showed that the presence of angina with mitral stenosis could be correlated with a low cardiac output and the severity of the stenosis, and was relieved by operation in all cases. Of the patients with congenital heart disease, less than 5 per cent these were primarilv patients had angina; with an “obstruction to the circulation of the blood,” such as aortic stenosis, pulmonic stenosis or primary pulmonary hypertension. Those patients with a shunt between the left and right side of the heart did not have angina, and Stuckey postulated that in these cases any existing obstruction to the circulation could be bypassed with reversal of the shunt. Thirtythree patients had standard exercise electrocardiograms with right-sided chest leads as well. Abnormal responses were best seen in left
446
Wagman
ventricular leads, even in those patients with right ventricular preponderance, but no correlation was noted with the degree of elevation of right ventricular or pulmonary arterial pressure. Unfortunately, no mention was made as to whether or not any of these patients was receiving digitalis. Stuckey postulated that the underlying mechanism was an inadequate coronary blood flow secondary to a low cardiac output. Although a chronically low resting cardiac output can affect resting coronary flow, we have seen brisk rises in coronary- flow on effort even when cardiac output failed to increase; the two are not necessarily related.r3 In their series of patients with congenital heart disease and angina pectoris, Ross and Baker44 found a common factor to be an elevated right ventricular pressure. This was noted in those subjects having a communication between the left and right side of the heart. They reported an abnormal electrocardiogram on effort in a 19 year old boy with a patent ductus arteriosus, pulmonary hypertension and angina pectoris, who showed normal coronary arteries postmortem. Other electrocardiographic findings were not presented in detail. Froment et a1.45 reported two cases of typical angina pectoris in which the etiology- was shown to be extensive chronic pulmonary arterial thrombosis. Lipiodol injection studies of the coronary arteries showed them to be free of obstruction in both cases. Our data, while preliminary, confirm the fact that angina does indeed exist in patients with predominantly “right-sided” lesions of the heart, and may occur in the presence of an intracardiac shunt. The presence of an abnormal right precordial lead exercise electrocardiogram, however, appears to bear no specific relationship to clinical angina, and no correlation could be made with studies of abnormal flow. Admittedly, this lack of correlation may be a reflection of the limitations of the commonly available methods of study in the right ventricle drains man. Normally, predominantly into the anterior cardiac veins, and the left ventricle predominantly into the coronary sinus. Under the conditions of acquired or congenital right ventricular hypertrophy, however, the coronary sinus may or may not drain a portion of the blood from the right ventricle. In addition, it is known that increased right ventricular pressure alone can In one coronary sinus outflow.4” increase patient (MR) with pentalogy of Fallot (studied at necropsy) injection medium from the left
et al. coronary artery appeared in the coronary sinus, and from the right coronary artery at the anterior cardiac veins. Despite right vcntricular hypertrophy and hypertension, coronary hemodynamics, as determined from the coronary sinus, were within normal limits. ,Abnormal coronary smus hemodynamics were seen, however, in a patient with isolated pulmonic stenosis (M J). It would be hazardous to draw conclusions from a single case, but in a patient without left ventricular disease, the combination of abnormal dynamics and abnormal right precordial lead exercise electrocardiogram suggests the possibility of right ventricular coronary insufficiency. The effect of digitalis on right precordial electrocardiographic responses to exercise, especially in the presence of a normal left-sided one, is not known at present. Right L,‘entricular Coronury Insrc@&enry: AA1though right wntricular hypertension was a common factor, no correlation was found with degree of elevation of pressure, the presence of clinical angina or an abnormal right precordial lead exercise test. Pulmonary hypertension, as opposed to right ventricular hypertension, on the other hand, was not present in many cases in our series or in those from England.” The positive right precordial Master tests are suggestive of right ventricular subendocardial ischemia, but as yet our data arc too limited to show whether we are indeed dealing with a functional right ventricular coronary insufficiency in these patients. The physiology of right and left coronary flow has been studied in the experimental animal. Right coronary flow occurs during both phases of the cardiac cycle in the normal right ventricle because of the obvious pressure differential between the coronary arteries and the right ventricle.“” With right ventricular hypertension, this pressure difference is decreased or eradicated curtailing systolic during sy-stole, markedly coronary flow. The loss of the systolic phase means that the diastolic coronary flow rate is This vasodilatation almost doubled. encroaches on the right coronary arterial reserve at a time when intracavitary tension development (and ox)-gcn and coronary flow requirements) is increased, and total muscle mass to be perfused is increased (right ventricular hypertrophy). Thus, the stage is set for selective coronary insufficiency of the right ventricle. A further effect of decreased right ventricular systolic flow within the intramyocardial THE AMERlCAN
JOURNAL
OF CARDIOLOGY
Coronary collaterals from the right coronary artery in of left ventricular coronary the presence arterial disease is unknown. Right ventricular hypertension might be an important aggravating factor in left ventricular coronary insufficiency as well, possibly explaining the left precordial ischemic changes often seen with acute car pulmonale.
Insufficiency
4.
5.
SUMMARY
One hundred and fourteen patients have been studied by means of coronary sinus catheterization, of whom sixty-eight were examined during both rest and exercise. All had resting electrocardiograms and all those studied during exercise had standard exercise two-step tests as well. In thirty-seven undigitalized patients there was a good correlation between the results of the exercise electrocardiogram and characterization of coronary hemodynamics. Digitalis was a recurrent factor preventing interpretation of the exercise electrocardiogram. No correlation was found between chronic S-T segment depression in the electrocardiogram and the coronary venous oxygen saturation. A small group of patients with abnormal right precordial lead exercise tests is described. No correlation could be found with clinical pain or with coronary flow dynamics. Although pulmonary hypertension was uncommon, right ventricular hypertension was seen in all patients. ACKNOWLEDGMENTS The authors are indebted to Harold D. Levine for his skillful interpretations of the electrocardiograms in this study, to Raghaven Amarasingham, Thomas E. Woerner, Jean Smith and Eduardo Salazar for aid in performing the many exercise tests, to William B. Hood, Jr. for furnishing the data from England, and to Judith Roussel, Roslyn Rosenberg, Ann S. Doherty and Eunice Ward for laboratory and secretarial work essential to this study. REFERENCES 1. BAY~EY, R. H., LADUE, J. S. and YORIC, D. J. Electrocardiographic changes (local ventricular ischemia and injury) produced in the dog by temporary occlusion of a coronary artery, showing a new stage in the evolution of myocardial infarction. Am. Heart J., 27: 164, 1944. 2. WECRIA, R., SEGERS,M. and KBATING, R. P. Relationship between the reduction in coronary flow of electrocardiographic and the appearance changes. Am. Heart J., 38: 90, 1949. 3. KIMWRA, E., SUZUKI, N., KANAZAWA, T., ITO, Y., HARIGAI, N., YAMAMOTO, F., KUMAGAI, S., MARCH 1962
6.
7.
8.
9.
10.
11.
12. 13.
14.
15.
16.
17.
18. 19.
447
SUZUKI, Y. and OBARA, F. Experimental studies on coronary insufficiency and coronary occlusion. I. On the relation of coronary blood flow and S-T deviation in the electrocardiogram. Tohoku J. Exjvr. Med., 66: 25, 1957. GOODALE, W. T. and HACKEL, D. Measurement of coronary blood flow in dogs and man from rate of myocardial nitrous oxide desaturation. Circulation Res., 1 : 502, 1953. VAN SLYKE, D. D. and NEILL, J. M. Determination of gases in blood and other solutions by vacuum extraction and manometric measurement. J. Biol. Chem., 61: 523, 1924. MASTER, A. M. Two-step exercise electrocardiogram test for coronary insufficiency. .4nn. Int. iwed., 32: 842, 1950. MATTINGLY, T. W., FANCHER, P. S., BAUER, F. L. and ROBB, G. P. The value of the double standard two-step exercise tolerance test detecting coronary disease in a follow-up study of 1000 Research Report, Army military personnel. Medical Service Graduate School, Washington, D. C., AMSGS-21-54, September 1954. MATTINGLY, T. W., ROBB, G. P. and MARKS, H. H. Electrocardiographic stress tests in suspected coronary disease. FValter Reed Army Institute of Research, Washington, D. C., WRAIR-75-57, May 1957. GORI_IN, R., BRACHFELD, N., MACLEOD, C. and BOPP, P. Effect of nitroglycerin on the coronary circulation in patients with coronary artery disease or increased left ventricular work. Circulation, 19: 705, 1959. LIEBOW, I. M. and FEIL, H. Digitalis and the normal work electrocardiogram. Am. Heart J., 22: 683, 1941. MESSER, J. V., LEVINE, H. J., NEILL, W. A., WAGMAN, R. J. and GORLIN, R. Reflex coronary constriction; its possible existence in human congestive heart failure. Circulation, 22: 789, 1960. HOOD, W. B. and DAIZY, R. Personal communication. MESSER, J. V., WAGMAN, R. J., LEVINE, H. J., NEILL, W. A., KRASNOW, N. and GORLIN, R. Patterns of myocardial oxygen extraction during rest and exercise. J. Clin. Inuest., in press. GERTLER, M. M., HOFF, H. E. and HUMM, D. G. The acid tolerance of the dog heart. Am. J. Physiol., 146: 478, 1946. WINKLER, .4. W., HOFF, H. E. and SMITH, P. K. Electrocardiographic changes and concentration of potassium in serum following intravenous injection of potassium chloride. Am. J. Physiol., 124: 478, 1938. Yu, I’. N., YIM, B. J. B. and STANFIELD,C. A. Hyperventilation syndrome. Arch. I&. Med., 103: 902, 1959. HIRVONEN,M. Uber die Wirkung des Bariums auf das Her;: auf Grund zweier Vergiftungsfslle. Actn med. Scandinau., 119: 112, 1944. CIIAPMAN, D. W. and SHAFFER, C. F. Mercurial diuretics. Arch. Int. Med., 79: 449, 1947. HOUIX, D. B., WFX, M. H., BROWN, E. B., JR. and CAMPBELL.G. S. Influence of respiratory acidosis on electrocardiogram and pressor responses to and metaraminol. epinephrine, norepinephrine, Proc. Sot. Exfier. Biol. @ Med., 94: 561, 1357.
448
Wagman
20. PRINZMETAL,M., EKMEKCI,A., TOYOSHIMA,H. and KWOCZNSKI,J. K. Angina pectoris. III. Demonstration of a chemical origin of S-T deviation in classic angina pectoris, its variant form, early myocardial infarction and some non-cardiac conditions. Am. J. Cardiol., 3: 276, 1959. 21. TANDOWSKY, R. M., ANDERSON,N. and VANDEVENTER, J. K. An electrocardiographic and clinical study of various so-called cardiac drugs. Am. Heart J., 28: 298, 1944. 22. LARSEN, K., NEUKIRCH, F. and NIELSEN, N. A. Electrocardiographic changes in normal adults following digitalis administration. Am. Heart J., 13: 163, 1937. 23. ASCHENBRENNER,R. Beitrag zur Wirkung hoher intravenijser Digitalisgaben bei paroxysmaler Tachykardie. Klin. Wchnschr., 14: 1313, 1935. 24. WOLFERTH, C. C., BELLET, S., LIVEZEY, M. M. and MURPHY, F. D. Negative displacement of the RS-T segment in the electrocardiogram and its relationship to positive displacement. Am. Heart J., 29: 220, 1945. 25. DEARING, W. H., BARNES, A. R. and ESSEX, H. E. Experiments with calculated therapeutic and toxic doses of digitalis. I. Effects on the myocardial cellular structure. Am. Heart J., 25: 649, 1943. 26. GOLDBERGER, E. Unipolar Lead Electrocardiography. Philadelphia, 1949. Lea & Febiger. 27. WENDT, L. Die ST-Depression des Elektrokardiogramms ein Symptom des anaeroben Herzstoffwechsels. Arch. f. Kreislaufforsch, 8 : 74, 1941. 28. WAKIM, K. G., ESSEX, H. E. and MANN, F. C. The effects of whole bile and bile salts on the innervated and the denervated heart. Am. Heart J., 20: 486, 1940. 29. BING, R. J., MARAIST, F. M., DAMMANN,3. F., JR., DRAPER, A., JR., HEIMBECKER,R., DALEY, R., GERARD, R. and CALAZEL, P. Effect of strophanthus on coronary blood flow and cardiac oxygen consumption of normal and failing human hearts. Circulation, 2: 513, 1950. 30. SAYEN, J. J., SHELDON,W. F., PIERCE, G. and Kuo, Polarographic oxygen, the epicardial P. T. electrocardiogram and muscle contraction in experimental acute regional ischemia of the left ventricle. Circulation, Res., 6: 779, 1958. 31. SAYEN, J. J., KATCHER, A. H., SHELDON,W. F. and GILBERT, C. M., JR. The effect of levarterenol on polarographic myocardial oxygen, the epicardial electrocardiogram and contraction. Circulation Res., 8: 109, 1960. 32. KOBAYASHI, T., ITO, Y., NAKANISHI, K., ITO, I., TSUWKI, H., ATSUMI, T., OTA, A., HARUMI, K., YASUDA, H. and WATANABE, M. Studies on
et al.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
myocardial metabolism by coronary sinus catheterization in man. Relationship of myocardial metabolism to electrocardiogram and cardiac size. Japanese Heart J., I: 157, 1960. RAAB, W. Adreno-sympathogenic heart disease: Neurohormonal factors in pathogenesis and treatment. Ann. Znt. Med., 28: 1010, 1948. GAZES, P. C., RICHARDSON,J. A. and WOODS, E. F. Plasma catechol amine concentrations in myocardial infarction and angina pectoris. Circulation, 19: 675, 1959. BLUMGART,H. L., SCHLESINGER, M. J. and DAVIS, D. Studies on the relation of the clinical manifestations of angina pectoris, coronary thrombosis and myocardial infarction to the pathological findings. Am. Heart J., 19: I, 1940. RUMBALL, C. A. and ACHESON, E. D. Electrocardiograms of healthy men following exercise. Brit. Heart J., 22: 415, 1960. POSSELT, A. Die klinische Diagnose der Pulmonalarteriensklerose, Vorlaufige Mitteilung. M&Zcfzen med. Wchnschr., 55: 1625, 1908. WHITE, P. D. The clinical significance of cardiac pain. In: Diseases of the Coronary Arteries and Cardiac Pain, p. 269. Edited by Levy, R. L. New York, 1936. MacMillan Co. BURGESS,A. M., JR. and ELLIS, L. B. Chest pain in patients with mitral stenosis with particular reference to so-called “hypercyanotic angina.” NrrC1 Enpland J. Med., 226: 937, 1942. VIAR, W. N. and HARRISON, T. R. Chest pain in association with pulmonary hypertension; its similarity to the pain of coronary disease. Circulation, 5: 1, 1952. MULLER, 0. and R@RVIK, K. Haemodynamic consequences of coronary heart disease. Brit Heart J., 20: 302, 1958. HOWARTH, S. and Lawn, J. B. The mechanism of effort syncope in primary pulmonary hypertension and cyanotic congenital heart disease. Brit. Heart J., 15: 47, 1953. STUCKEY, D. Cardiac pain in association with mitral stenosis and congenital heart disease. Brit. Heart J., 17: 397, 1955. Ross, R. S. and BAKER, B. M. Right ventricular hypertension as a cause of angina pectoris. circulation, 22: 801, 1960. FROMENT, R., LEN&GRE, J., GERBAUX, A. and HIMBERT, J. L’angine de poitrine d’effort par thrombose arterielle pulmonaire chronique. Arch. ma1 coew, 53: 361, 1960. GREGG, D. E. The Coronary Circulation in Health and Disease, p. 227. Philadelphia, 1950. Lea & Febiger.
THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Insufficiency
in Man
and Electrocardiographic
Correlation*
RICHARD J. WAGMAN, M.D.,HERBERT J.LEVINE,M.D.,JOSEPH V. MESSER, M.D., WILLIAM A. NEILL,M.D.,NORMAN KRASNOW, M.D. and RICHARD GORLIN, M.D., F.A.C.C. Boston,
M
Massachusetts
whenever YOCARDIAL ISCHEMl.4 occurs there exists a discrepancy between the available oxygen supply and the work requirements of the heart muscle. This can be due to narrowing of coronary arteries by occlusive disease or to a decrease in the oxygen-carrying capacity of the blood, as in anemia, or when tissue utilization is blocked, as by cyanide. It may also be due to a relative insufficiency of the arterial tree, as seen in myocardial hypertrophy or when the myocardial energy requirements exceed the maximal flow capacity of the coronary vascular bed. It has long been known that ischemia is associated with electrocardiographic changes. Bayley’s work1 on the evolution of the classic ischemic electrocardiographic pattern in the dog is perhaps the most well known. Only a few attempts have been made, however, to correlate the degree of “coronary insufficiency” with the development of electrocardiographic changes. Wegria2 in 1949 studied this problem by altering directly measured coronary flow in the dog by means of an adjustable clamp. A reduction of coronary flow to 65 to 90 per cent of control values did not generally affect the electrocardiogram, while a reduction of from 30 to 65 per cent produced “slight” changes and a reduction to 30 per cent or less of control flow always produced “marked” changes. Kimura et a1.,3 with similar technics, demonstrated depression of the S-T segment on reduction of coronary flow to one-third the “normal” resting value. Evaluation of myo-
cardial hypoxia was not made in these investigations. Intracellular oxygen tension is equal to or less than the effluent venous oxygen tension. Thus, analysis of venous oxygen tension or saturation can give some idea of at least the highest value within the cell. In the case of the heart, therefore, coronary venous oxygen saturation (allowing for pH) reflects average left ventricular myocardial oxygen tension. It is the purpose of this paper to analyze the relationship, if any, between coronary venous oxygen saturation and the electrocardiographic patterns recorded in a large group of patients. MATERIALS AND METHODS One hundred and fourteen patients have been studied by the technic of coronary venous and systemic arterial catheterization. Coronary blood flow was determined by the nitrous oxide techni@; coronary arteriovenous oxygen differences were determined by the method of van Slyke and Neill.5 Observations were made in the resting state in all. Sixty-eight patients were examined during both rest and a 6 to 8 minute period of supine leg exercise sufficient to raise total body oxygen consumption two to three times the resting level. Multiple coronary venous oxygen saturations were determined before, at various times during, and again following effort. All patients had electrocardiograms taken at rest; all who underwent coronary flow studies during exercise had standard exercise electrocardiograms (Master two-step tests). Because of the correlation between their electrocardiographic findings and long-term follow-up study of patients, we have elected to use the criteria of Mattingly et al.‘**-nonjunctional S-T
* From the Medical Clinics of Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts. This work was supported by grants from the U. S. Public Health Service (N.I.H. H-2637) and the Massachusetts Heart Association (No. 390). MARCH
1962
439
Wagman
440
et al.
36 t
.-E
z
5 ‘0
0-l
El
m30 =‘
‘.
YCORONARY
0
/INSUFFICIENCY \
: z 3
I’
\ \
? : 0 : 0
/ ‘\.
24REST PRE- EXERCISE
I I
\
\
I
I
3
5
EXERCISE
\r
t 7
(Min.)
REST POST- EXERCISE
venous oxygen saturation during exercise. The 1. Change in coronary normal group shows remarkable constancy of the coronary venous oxygen saturation. In those with coronary insufficiency, it fell to a low of 23 per cent below control levels on exercise (p < .005). FIG.
segment depression of 0.5 mm. or more-as our only Patients were lurther evidence of abnormality. classified and analyzed according to whether they were receiving digitalis. RESULTS
For the purposes of this study we have classified our patients with coronary flow studies into three broad categories as follows : normal, abnormal and equivocal. Since it has been shown previously9 that coronary hemodynamics in the presence of diffuse coronary disease may be within normal limits at rest, only those patients who were stressed have been classified into these groups. The normal group had an average of 40 per cent increase in coronary blood flow with exercise (- 8 to +162 per cent), as compared with 34 per cent in the abnormal group (- 5 to +141 per cent). Also demonstrated was a 30 per cent decrease in diastolic vascular resistance (as a measure of coronary vasodilatation) in the normal group (+8 to -82 per cent) and a fall in the “coronary” group of 21 per cent (+14 to - 62 per Coronary arteriovenous oxygen differcent). ence showed no consistent pattern in the normal group (+lO to -23 per cent) but widened 8 per cent (+4 to +12.8 per cent) in the group with coronary arterial disease. The myocardial
oxygen extraction coefficient (A-Vol/AO* was essentially unchanged (-3 per cent relative to resting level) in the normal group, but increased considerably (+12 per cent relative to resting value) in 83 per cent of the coronary In the normal group patients (p < .005). coronary venous oxygen saturation was remarkably constant (Fig. l), but decreased in 83 per cent of the patients with coronary disease. The fall was 23 per cent below control levels in twenty-one of the twenty-nine cases (an absolute decrease in saturation of 5 per cent or more) (p <.005). This latter finding was the one of most importance for this study in defining physiologic coronary insufficiency. One patient could not be clearly classified on the basis of the previously mentioned criteria and was, therefore, considered to be “equivocal.” Correlation
of
Coronary
Hemodynamics
and
Exer-
*This coefficient reflects the amount of oxygen removed per milliliter of arterial blood presented to the A decrease in the coefficient indicates myocardium. less removal and more blood flow in relation to demand; conversely, an increase indicates more oxygen removal and relatively less blood flow in relation to demand. If exercise produced an absolute fall in coronary venous oxygen saturation of 5 per cent or greater or an absolute increase of myocardial oxygen extraction percentage of 3 per cent or greater, this was considered abnormal.i3 THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Coronary
Insufficiency
441
TABLE I Correlation
TABLE II Correlation of the Master Exercise Test with Coronary Physiology in the Undigitalized Patient
of the Master Exercise Test with Coronary Physiology Exercise
Hemodynamics
No. Patients
Electrocardiogram
Normal
Hemodynamics
Abnormal
Equivo-
11 22
1 1
Normal Abnormal Equivocal
2
Total
Normal Abnormal Equivocal
37 30 1
25 7 1
...
Total
68
33
33
with
15
Angina
/\.
.
1962
21 15 1
16 5 1
5 10 .
37
22
15
on Digitalis
/
8
biARCH
Abnormal
Pectoris
Abnormal Correlation
Normal
ma1 hemodynamics had an abnormal tracing. If one eliminates those patients receiving digitalis, there appears to be an even better correlation between the exercise electrocardiogram and hemodynamic evaluation of coronary physiology (Table II). Of this group of thirty-seven patients, twenty-one had flow studies within normal limits; i.e., flow was adequate to oxygen needs and coronary venous saturation was unchanged. Sixteen oxygen of these twenty-one (76 per cent) had normal Master exercise tests. Of the fifteen patients with abnormal flow studies, ten had abnormal exercise electrocardiograms. One patient had equivocal flow studies, with a normal exercise test. A total of twenty-nine patients had definite angina pectoris. Of these, twenty-six had exercise electrocardiograms in addition to coronary flow studies. Twenty of these twenty-six had abnormal coronary hemodynamics (Fig. Fifteen of the twenty-six were not receiving 2).
9 *bnorma1/<\
FIG. 2.
Exercise Electrocardiogram
Patients
Cd
Table I shows the corcise Electrocardiograms: relation between the Master test and the coroTwennary circulation in sixty-eight patients. ty-five of thirty-seven patients with normal hemodynamics had normal exercise electrowhile eleven were abnormal. cardiograms, Twenty-two of thirty patients with abnormal hemodynamics had abnormal exercise tolerance seven were within normal limits. As tests; previously noted, however, digitalis can affect the exercise electrocardiogram with the production of S-T segment depressions, making interpretation either difficult or impossible.‘0 Nevertheless, it is to be noted that if the exercise electrocardiogram remained within normal limits despite digitalization, 76 per cent (twenty-five of thirty-three patients) had normal hemodyAlso, despite the influence of digitalis namics. on the exercise electrocardiogram in the remaining patients, 73 per cent of those with abnormal hemodynamics had an abnormal electrocardiogram while only 30 per cent of those with nor-
Of 26 Patients
No.
20 Hemodynamics
between angina pectoris, exercise test and coronary physiology.
Wagman
442 S-T
20 or <
21 to 25
SEGMENT
26 to 30
DEPRESSION
31 to 35
Coronary
36 to 40 Venous
et al. NORMAL
11
Oxygen
SEGMENT
r
20 or <
41 or >
S-T
21 to 25
26 to 30
Saturation
31 to 35
36 to 40
oh
FIG. 3. Relation of S-T segment to coronary UP~DUSoxygen saturation. Fifty-eight patients of a group of 114 had S-T segment depression at rest. Twenty-five of these (43 per cent) had coronary venous oxygen saturations of less than 26 per cent. Of the fifty-six with normal S-T segments at rest, eleven (20 per cent) had coronary venous oxygen saturations of less than 26 per cent (p < .02).
and nine of these fifteen (60 per cent) had abnormal exercise electrocardiograms. Of this group of nine with both clinical angina pectoris and an abnormal exercise electrocardiohad abnormal eight (89 per cent) gram, flow studies as well. Correlation of Coronury Hemodynamics and Electrocardiograms at Rest: Those patients studied only at rest were grouped initially into two categories: those with and those without S-T The groups segment depression in any lead. were further subdivided according to whether These the patient was receiving digitalis. electrocardiographic changes were then compared with the coronary venous oxygen satuNo attempt was made to corration alone. relate the resting electrocardiogram with the level of coronary flow because even in the presence of coronary arterial disease, this may be within normal limits at rest (uide infru). Figure 3 illustrates the relationship in the resting subject between the electrocardiogram and the coronary venous oxygen saturation (an index of over-all myocardial oxygenation). Fifty-eight patients of a group of 114 had an abnormal electrocardiogram at rest as characterized by persistent depression of the S-T segment on any lead. Twenty-five of these (43 per cent) had coronary venous oxygen By consaturations of less than 26 per cent. trast, of fifty-six patients with normal electro-
digitalis,
cardiograms at rest, eleven (20 per cent) had coronary venous oxygen saturations of less than 26 per cent. Thus, those patients \rith S-T segment depression had lower coronary venous oxygen saturations slightly more often than did those with normal electrocardiograms. This difference is statistically significant (p However, coronary venous oxygen < .02). saturation is decreased as part of the vasoconstrictor response to low output congestive heart failure or mitral stenosis.” Also, it is in these latter conditions that digitalis is used most frequently with its attendant effects on Thus, the correlation the electrocardiogram. be fortuitous. However, the average may coronary venous oxygen saturation was 28.7 per cent with little variation between groups (Table III). For the individual patient, it was impossible to predict the coronary venous oxygen saturation from the electrocardiogram and vice versa. Right-Sided Cardiac Lesions: Of the sixty--eight abpatients studied, sixteen had circulatory normalities affecting primarily the right side of the heart. They presented no evidence of coronary arterial disease, aortic valvular disor hypertension. The lesions in the ease right side of the heart ranged from pure mitral stenosis to pulmonic stenosis to pentalogy of Fallot. These patients, in addition to the routine studies, had right chest leads recorded THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Coronary TABLE
S-T
Segment
Insufficiency elevated
III
Depression at Rest Versus 0 xygen Saturation
Coronary
Venous
exercise In
(‘Z)
IS-T segment depression 42 on digitalis 16 off digitalis Average saturation Normal S-T segment 8 on digitalis 48 off digitalis Average saturation Total average saturation
in only
one
and
failed
to rise with
in the other patients. a
group
of
forty-seven
patients
with
predominant “right-sided lesions” studied at St. Thomas’ Hospital, London by Hood and Daley,‘* only seven had abnormal results of the right precordial lead Master tests. In this
O? Saturation
Segment
443
23.2 28.2 26.8
series also, no correlation tween an abnormal right
28.2 31.2 30.7 28.7
level of right ventricular pressure or both. No studies were performed.
ter
test,
the
presence
could be found beprecordial lead Mas-
of clinical
angina,
the
or pulmonary arterial coronary blood flow
COMMENTS Electrocardiographic abnormalities considered to be representative of myocardial ischemia could not be specifically correlated with decreased coronary venous oxygen saturation per se. This is not surprising. First, it must be appreciated that coronary venous blood comes from areas which may be unevenly perfused in relation to need, particularly with coronary disease. Ischemic areas of functioning muscle, by extracting more oxygen than surrounding areas, will tend to lower coronary venous oxygen content. Areas of scarring usually have a miniscule blood supply. It has been suggested, however, that on occasion large enough blood vessels may traverse these scars to act as small arteriovenous shunts, tending to raise coronary venous oxygen content. Coronary venous oxygen saturation undoubtedly represents the over-all resultant of
as part of their standard Master exercise test. From this group, patients with S-T segment depression of 0.5 mm. or more in any right precordial lead were separated in an attempt to relate an abnormal response to a possible common hemodynamic factor. Four patients had abnormal results from the right precordial lead exercise tolerance test. One of these, a patient with severe mitral insufficiency and pulmonary hypertension, had depression of S-T segments in leads over both left and right precordium (Table IV). The abnormality electrocardiographic could not be correlated with the presence or absence of angina, or with abnormal coronary flow studies. Furthermore, although all patients had elevated right ventricular pressures (in the range of 100 mm. Hg), pulmonary arterial pressure was
TABLE Positive
Right
-
Patirrrt
IV
Precordial
Lead
T Diagnosis
Exercise
Test
Pressure
Angina
Hemodynamic Pattern
Right Ventricle
_ MR hl.1 EL HR”
Pentalogy of Fallot Pulmonic stenosis Tetralogy of Fallot Mitral insufficiencyt; pertension
* Abnormal t Rheumatic MARCH
1962
right- and left-sided heart disease.
precordial
hy-
lead
Normal Abnormal Normal Normal
Yes No Yes
exercise
test.
100/3 135/o 110/o 98/l 1
Hg)
Pulmonary Artery (mean) ___ Rest
? pulmonary
(mm.
7 8 7 64
Exercise
12 8 11 90
444
Wagman
these opposing effects. While sampling at multiple points along the great cardiac vein in various types of heart disease has shown remarkable uniformity of oxygen content,r3 regional changes may be undetected by coronary venous sampling. This is due to the following factors: (1) the ischemic contribution may be very small relative to the total left ventricular coronary flow ; and (2) increases through functioning shunts may occur to counterbalance a decrease in oxygen saturation of blood from an ischemic region. Hence, any measurable abnormality should be regarded as reflecting the end result of a diffuse arterial disease process. It can be calculated that due to the flow-extraction ratio of the myocardium for oxygen, a 10 per cent increase in arteriovenous oxygen extraction is roughly equivalent to a 12 per cent insufficiency of over-all coronary flow, with the implicit understanding that given areas may receive totally different degrees of perfusion. Conversely, it is well known that numerous drugs, changes in osmotic pressure, pH, hyperventilation, ionic imbalance and certain heavy metals can cause S-T segment depression in the electrocardiogram without necessarily producing myocardial hypoxia.14-20 Digitalis, for example, is one of the commonest causes of a depression of the S-T segment. This may be seen as early as 10 minutes following an intravenous injection of digitoxin.” In the case of the whole leaf, this may last as long as 2 to 3 weeks.= Even after complete disappearance of digitalis-induced S-T segment depression, doses of digitalis which would have been completely without effect alone, now cause this change to reappear.% The etiology of these electrocardiographic changes is unknown. The drug affects the monophasic action potential of the ventricle, the T wave, RS-T segment and the duration of the Q-T interval.24 In animals large doses of digitalis have produced myocardial necroses in the subendocardial layers of the left ventricle.25 However, the doses of digitalis required have been in the toxic range. Other factors such as loss of potassium by the heart muscle celP or a change in myocardial metabolism to anaerobic pathway? have been postulated as possible causes of the electrocardiographic changes. Interestingly enough, dehydrocholic acid (Decholin@) causes S-T segment depression also, and it has been suggested that this is due to its structural similarity to the digitalis drugs.28 The explanation for the specific effect which digitalis has on exercise
et al. electrocardiograms is even less clear. As shown by Bing et al., 2g digitalization has no effect on coronary blood flow, degree of coronary vasodilation, coronary venous oxygen saturation or oxygen consumption of the left ventricle. While electrocardiographic and coronary venous oxygen abnormalities showed random variation at rest, changes in these parameters on exercise went hand in hand. Although there was a suggestive relationship within the total group, the correlation became even better if the digitalized patients were excluded. The coincidence between a falling coronary venous oxygen saturation on exercise and an abnormal Master exercise test should not, however, imply that the former is necessarily a cau.ce of the latter, but rather that both phenomena may reflect a common background, i.e., a diffuse occlusive arterial disease process. Sayen et a1.,30 using the polarographic oxygen electrode, showed that following the experimental occlusion of a coronary artery there is a rapid fall in myocardial oxygen tension. Electrocardiographic changes, however, rarely appeared before the period of rapid oxygen change was at least half over, and continued even after the myocardial oxygen tension reached stable levels in the range of less than 25 per cent of control values in the central area of ischemia, and 25 to 75 per cent in the adjacent tissue zones. What additional mechanisms are operative here is uncertain, but alterations in the characteristics of the myocardial cell membrane, potassium or other ionic shifts, glycolysis, or a have been combination of such processes postulated to explain the electrocardiographic changes.30-32 Mechanisms of Angina Pectoris: Even more difficult to explain, and not at all clarified by is the nature of the underlying our data, mechanism producing clinical angina pectoris. Although increased plasma concentrations of norepinephrine and epinephrine have been reported in patients with myocardial infarction and angina pectoris on effort,3s,34 as seen in Table v, in a small group, there was no significant difference between the controls and those patients with clinical angina. Likewise, excess lactate production as evidence of anaerobic glycolysis was demonstrated in only two patients of this seriesi Myocardial serum potassium studies have been inconclusive thus far. Not only need there be no specific correlation between degree of heart damage (as seen in the pathologic specimen) and the development of THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Coronary TABLE v Blood
Catechols
in Patients With Pectoris
Subject
Controls (10 patients) Rest Exercise Angina Pectoris (7 patients) Rest Exercise
and Without
Epinephrine (pg./L.)
Angina
Norepinephrine (rg./L.)
0.8 0.6
2.4 2.5
0.5 0.3
2.5 2.9
but also between physiologic coronary inadequacy as measured by our technics and the development of pain. Furthermore, there is no necessary relationship between the development of electrocardiographic changes following exercise and the presence of clinical angina pectoris. Rumba11 and Acheson, in a study of 660 apparently healthy patients without clinical evidence for coronary or other forms of heart disease, showed that 45 (6.8 per cent) had nonjunctional S-T segment depression in their exercise electrocardiograms. This was noted primarily in patients over the age of 40. One might wonder whether or not, even in the absence of clinical pain, these subjects did indeed have an underlying functional inadequacy of the coronary circulation. Conversely, it would be interesting to determine if the prognosis is better in angina1 patients with a normal exercise electrocardiogram or exercise coronary hemodynamics or both than in those with frank abnormalities. It is interesting that angina pectoris occurs primarily in the “well-functioning” heart and tends to disappear with the onset of heart failure. Thus, it is likely that pain may originate from patchy areas of ischemic myocardium. Although the presence of such patchy ischemic areas may be undetected by the currently employed stress test, it is interesting to speculate on the possible role of such regions in the production of clinical angina pectoris. In response to stress (which drives the “whole heart”) as cardiac tension development increases, the ischemic area may “fall behind” in coronary flow and oxygen consumption. The stage is thus set for pain, but the over-all measured cardiac function is unaffected and may not be detected by our relatively crude “averaging” methods for coronary venous angina,s5
MARCH 1962
Insufficiency
445
oxygen saturations or the cruder coronary flow methods (nitrous oxide). Right-Sided Angina: The concept of rightsided angina is not new. Posselt,37 in one of the earliest statements on the subject, thought that the angina1 pain in a patient with mitral stenosis may have been due to distension of the pulmonary arteries, caused by pulmonary arteriolar spasm. White,38 in 1936, found that angina was rare in the presence of mitral stenosis except in the older age group in which there might be a superimposed coronary atherosclerosis. In 1942 Burgess and Ellis89 concluded that the pain originated from the myocardium was due to a relative anoxia and was associated with a decreased cardiac output which in turn caused impairment of coronary blood flo~.~~ All of their patients had right ventricular hypertrophy. No changes were noted in the limb leads of the electrocardiogram during attacks. Viar and Harrison40 in 1952 revived the concept of pain secondary to distension of the pulmonary artery itself, as in migraine, in a study of six patients with pulmonary hypertension and pain in the chest. They did not rule out coronary insufficiency of the right ventricle, but suggested that failure of the pain to respond to nitroglycerin was against this mechanism, although the drug, among other actions, does lower pulmonary arterial mean pressure.41 No exercise electrocardiogram or catheter studies were presented. Howarth and Lowe42 in 1953 reported the case of a patient with primary pulmonary hypertension with effort syncope, and showed the development of ischemic S-T segment depression in lead Vi on exercise. Stuckeyh3 in an excellent review showed that the presence of angina with mitral stenosis could be correlated with a low cardiac output and the severity of the stenosis, and was relieved by operation in all cases. Of the patients with congenital heart disease, less than 5 per cent these were primarilv patients had angina; with an “obstruction to the circulation of the blood,” such as aortic stenosis, pulmonic stenosis or primary pulmonary hypertension. Those patients with a shunt between the left and right side of the heart did not have angina, and Stuckey postulated that in these cases any existing obstruction to the circulation could be bypassed with reversal of the shunt. Thirtythree patients had standard exercise electrocardiograms with right-sided chest leads as well. Abnormal responses were best seen in left
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ventricular leads, even in those patients with right ventricular preponderance, but no correlation was noted with the degree of elevation of right ventricular or pulmonary arterial pressure. Unfortunately, no mention was made as to whether or not any of these patients was receiving digitalis. Stuckey postulated that the underlying mechanism was an inadequate coronary blood flow secondary to a low cardiac output. Although a chronically low resting cardiac output can affect resting coronary flow, we have seen brisk rises in coronary- flow on effort even when cardiac output failed to increase; the two are not necessarily related.r3 In their series of patients with congenital heart disease and angina pectoris, Ross and Baker44 found a common factor to be an elevated right ventricular pressure. This was noted in those subjects having a communication between the left and right side of the heart. They reported an abnormal electrocardiogram on effort in a 19 year old boy with a patent ductus arteriosus, pulmonary hypertension and angina pectoris, who showed normal coronary arteries postmortem. Other electrocardiographic findings were not presented in detail. Froment et a1.45 reported two cases of typical angina pectoris in which the etiology- was shown to be extensive chronic pulmonary arterial thrombosis. Lipiodol injection studies of the coronary arteries showed them to be free of obstruction in both cases. Our data, while preliminary, confirm the fact that angina does indeed exist in patients with predominantly “right-sided” lesions of the heart, and may occur in the presence of an intracardiac shunt. The presence of an abnormal right precordial lead exercise electrocardiogram, however, appears to bear no specific relationship to clinical angina, and no correlation could be made with studies of abnormal flow. Admittedly, this lack of correlation may be a reflection of the limitations of the commonly available methods of study in the right ventricle drains man. Normally, predominantly into the anterior cardiac veins, and the left ventricle predominantly into the coronary sinus. Under the conditions of acquired or congenital right ventricular hypertrophy, however, the coronary sinus may or may not drain a portion of the blood from the right ventricle. In addition, it is known that increased right ventricular pressure alone can In one coronary sinus outflow.4” increase patient (MR) with pentalogy of Fallot (studied at necropsy) injection medium from the left
et al. coronary artery appeared in the coronary sinus, and from the right coronary artery at the anterior cardiac veins. Despite right vcntricular hypertrophy and hypertension, coronary hemodynamics, as determined from the coronary sinus, were within normal limits. ,Abnormal coronary smus hemodynamics were seen, however, in a patient with isolated pulmonic stenosis (M J). It would be hazardous to draw conclusions from a single case, but in a patient without left ventricular disease, the combination of abnormal dynamics and abnormal right precordial lead exercise electrocardiogram suggests the possibility of right ventricular coronary insufficiency. The effect of digitalis on right precordial electrocardiographic responses to exercise, especially in the presence of a normal left-sided one, is not known at present. Right L,‘entricular Coronury Insrc@&enry: AA1though right wntricular hypertension was a common factor, no correlation was found with degree of elevation of pressure, the presence of clinical angina or an abnormal right precordial lead exercise test. Pulmonary hypertension, as opposed to right ventricular hypertension, on the other hand, was not present in many cases in our series or in those from England.” The positive right precordial Master tests are suggestive of right ventricular subendocardial ischemia, but as yet our data arc too limited to show whether we are indeed dealing with a functional right ventricular coronary insufficiency in these patients. The physiology of right and left coronary flow has been studied in the experimental animal. Right coronary flow occurs during both phases of the cardiac cycle in the normal right ventricle because of the obvious pressure differential between the coronary arteries and the right ventricle.“” With right ventricular hypertension, this pressure difference is decreased or eradicated curtailing systolic during sy-stole, markedly coronary flow. The loss of the systolic phase means that the diastolic coronary flow rate is This vasodilatation almost doubled. encroaches on the right coronary arterial reserve at a time when intracavitary tension development (and ox)-gcn and coronary flow requirements) is increased, and total muscle mass to be perfused is increased (right ventricular hypertrophy). Thus, the stage is set for selective coronary insufficiency of the right ventricle. A further effect of decreased right ventricular systolic flow within the intramyocardial THE AMERlCAN
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Coronary collaterals from the right coronary artery in of left ventricular coronary the presence arterial disease is unknown. Right ventricular hypertension might be an important aggravating factor in left ventricular coronary insufficiency as well, possibly explaining the left precordial ischemic changes often seen with acute car pulmonale.
Insufficiency
4.
5.
SUMMARY
One hundred and fourteen patients have been studied by means of coronary sinus catheterization, of whom sixty-eight were examined during both rest and exercise. All had resting electrocardiograms and all those studied during exercise had standard exercise two-step tests as well. In thirty-seven undigitalized patients there was a good correlation between the results of the exercise electrocardiogram and characterization of coronary hemodynamics. Digitalis was a recurrent factor preventing interpretation of the exercise electrocardiogram. No correlation was found between chronic S-T segment depression in the electrocardiogram and the coronary venous oxygen saturation. A small group of patients with abnormal right precordial lead exercise tests is described. No correlation could be found with clinical pain or with coronary flow dynamics. Although pulmonary hypertension was uncommon, right ventricular hypertension was seen in all patients. ACKNOWLEDGMENTS The authors are indebted to Harold D. Levine for his skillful interpretations of the electrocardiograms in this study, to Raghaven Amarasingham, Thomas E. Woerner, Jean Smith and Eduardo Salazar for aid in performing the many exercise tests, to William B. Hood, Jr. for furnishing the data from England, and to Judith Roussel, Roslyn Rosenberg, Ann S. Doherty and Eunice Ward for laboratory and secretarial work essential to this study. REFERENCES 1. BAY~EY, R. H., LADUE, J. S. and YORIC, D. J. Electrocardiographic changes (local ventricular ischemia and injury) produced in the dog by temporary occlusion of a coronary artery, showing a new stage in the evolution of myocardial infarction. Am. Heart J., 27: 164, 1944. 2. WECRIA, R., SEGERS,M. and KBATING, R. P. Relationship between the reduction in coronary flow of electrocardiographic and the appearance changes. Am. Heart J., 38: 90, 1949. 3. KIMWRA, E., SUZUKI, N., KANAZAWA, T., ITO, Y., HARIGAI, N., YAMAMOTO, F., KUMAGAI, S., MARCH 1962
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20. PRINZMETAL,M., EKMEKCI,A., TOYOSHIMA,H. and KWOCZNSKI,J. K. Angina pectoris. III. Demonstration of a chemical origin of S-T deviation in classic angina pectoris, its variant form, early myocardial infarction and some non-cardiac conditions. Am. J. Cardiol., 3: 276, 1959. 21. TANDOWSKY, R. M., ANDERSON,N. and VANDEVENTER, J. K. An electrocardiographic and clinical study of various so-called cardiac drugs. Am. Heart J., 28: 298, 1944. 22. LARSEN, K., NEUKIRCH, F. and NIELSEN, N. A. Electrocardiographic changes in normal adults following digitalis administration. Am. Heart J., 13: 163, 1937. 23. ASCHENBRENNER,R. Beitrag zur Wirkung hoher intravenijser Digitalisgaben bei paroxysmaler Tachykardie. Klin. Wchnschr., 14: 1313, 1935. 24. WOLFERTH, C. C., BELLET, S., LIVEZEY, M. M. and MURPHY, F. D. Negative displacement of the RS-T segment in the electrocardiogram and its relationship to positive displacement. Am. Heart J., 29: 220, 1945. 25. DEARING, W. H., BARNES, A. R. and ESSEX, H. E. Experiments with calculated therapeutic and toxic doses of digitalis. I. Effects on the myocardial cellular structure. Am. Heart J., 25: 649, 1943. 26. GOLDBERGER, E. Unipolar Lead Electrocardiography. Philadelphia, 1949. Lea & Febiger. 27. WENDT, L. Die ST-Depression des Elektrokardiogramms ein Symptom des anaeroben Herzstoffwechsels. Arch. f. Kreislaufforsch, 8 : 74, 1941. 28. WAKIM, K. G., ESSEX, H. E. and MANN, F. C. The effects of whole bile and bile salts on the innervated and the denervated heart. Am. Heart J., 20: 486, 1940. 29. BING, R. J., MARAIST, F. M., DAMMANN,3. F., JR., DRAPER, A., JR., HEIMBECKER,R., DALEY, R., GERARD, R. and CALAZEL, P. Effect of strophanthus on coronary blood flow and cardiac oxygen consumption of normal and failing human hearts. Circulation, 2: 513, 1950. 30. SAYEN, J. J., SHELDON,W. F., PIERCE, G. and Kuo, Polarographic oxygen, the epicardial P. T. electrocardiogram and muscle contraction in experimental acute regional ischemia of the left ventricle. Circulation, Res., 6: 779, 1958. 31. SAYEN, J. J., KATCHER, A. H., SHELDON,W. F. and GILBERT, C. M., JR. The effect of levarterenol on polarographic myocardial oxygen, the epicardial electrocardiogram and contraction. Circulation Res., 8: 109, 1960. 32. KOBAYASHI, T., ITO, Y., NAKANISHI, K., ITO, I., TSUWKI, H., ATSUMI, T., OTA, A., HARUMI, K., YASUDA, H. and WATANABE, M. Studies on
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