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Some considerations of coronary flow
Some Considerations of Coronary Flow By ROBERT B.
CASE AND ROBERT B. ROVEN
N THE SURFACE it seems illogical that a person with severely diseased coronary vessels should have a normal Coronary flow/ On further consideration, however, this should not surprise us greatly, since all evidence points to the subservience of flow to the oxygen needs of the myocardium, and the factors which govern this--even in severe coronary sclerosis--are unchanged.
O
RELATION BETWEEN CORONARYFLOW AND MYOCARDIALOXYGEN CONSUMPTION
D~erminants of Coronary Flow It is only recently that the fundamental determinants of coronary flow have been appreciated. Correlation had been attempted with such factors as cardiac output, mechanical work, myocardial oxygen consumption, aortic pressure, diastolic time, heart size, arterial oxygen content, and a host of other variables. The finding that appears to unify these seemingly diverse and tenu, ously connected variables is that coronary sinus oxygen content 2-4 remains the same regardless of the heart's physiological state, indicating that coronary flow is adjusted to maintain a constant myocardial oxygen value. A constant arteriovenous difference inevitably results in such a system, and hence it should be evident that alterations in coronary flow and myocardial oxygen consumption must proceed in a parallel manner. Changes in coronary flow thus reflect only changes in myocardial oxygen consumption. This system is exquisitely sensitive, reacting promptly to any intervention that may vary the oxygen concentration of the myocardial cell. It can be upset only by substances acting independently on the coronary bed, or by requiring of it responses that exceed its limits of reactivity. Determinant~ of Myo,cardial Oxygen Consumption The determinants of myocardial oxygen consumption itself have recently been clarified. In the past it was reasonably assumed that the work performed by the ventricle was closely related to the oxygen consumed, and this work was calculated in the strict physical sense as the integral of pressure and flow or, more simply, as the product of pressure and flow. Separation of these two factors in isolated heart experiments~,6 yielded the surprising result that myocardial oxygen consumption depended solely upon pressure generated by the ventricle and its frequency of so doing, and that oxygen consumption was unaffected by alterations in cardiac output. Thus, mechanical efficiency of the ventricle, calculated in the traditional manner, may vary greatly with changes in cardiac output. While data in the human being are not so complete, these findings appear to b e confirmed by From the Department of Medicine, St. Lukes Hospital, New York City. 45 PaOGR~SSIN CA~mOVASCVLAJaDISEASES,VOL. 6, No. 1 (JULY), 1963
46
CASE A N D ROVEN
the additional observation that oxygen consumption is also related to cardiac diameter. 7 A consideration of these factors together indicates that the determining factor in oxygen consumption, and thus in coronary flow, is the tension of the myocardial fiber created per unit of time, and that this may be elinieally estimated by observation of the cardiac rate and size, and the systolic pressure. Logically then, in a patient with coronary disease, there would be no reason to suspect a reduction in coronary flow unless these determinants of oxygen consumption were also reduced. Regarded from another view, it has been shown that when coronary flow is experimentally lowered, a fall in arterial pressure occurs until oxygen supply and demand are again in accord, s Not only is resting coronary flow normal in coronary disease, but patients so aflqieted also respond to exercise with an increase in flow equivalent to that in normal persons. Hence, flow measurements give no indication whatsoever of the degree of coronary patency or the accompanying marginal state of myocardial oxygenation. The best index of functional incompetence of the coronary vessels seems to lie in certain responses to stress. Coronary sinus blood usually shows both a fall in oxygen content with exercise, 3 which indicates exhaustion of the arteriolar dilating reserve, and the production of excess lactate, 9 which means that the heart is beginning to satisfy some of its energy requirements through anaerobic metabolism. The onset of angina, or changes in the S-T segment of the electrocardiogram after stress, also suggest inadequacy of the coronary dilatory reserve, although these responses are subiect to many other influences. It is also interesting to note that in other disease states, the measurement of coronary flow is of little value in assessing the adequacy of the coronary eirctdation, the severity of the disease, or even the diagnosis. In cardiac failure, ventrieular hypertrophy, coronary artery disease, hypertension, mitral stenosis, aortic insufficiency, and aortic stenosis the coronary flow, as determined by the nitrous oxide technique, is almost always within the normal rangeA 1~ It must be remembered that the nitrous oxide method, which has been used in nearly all human studies, is only capable of measuring flow per 100 Gin. of left ventricle; actual total flow in an enlarged heart may be many times normal. The reasons for this seeming "normalization" of coronary flow per unit mass are not clear, but it is evident that myocardial hypertrophy proportional to the increased total ecronary flow must occur. An increase in flow per unit of muscle mass has been seen only in such acute situations as exercise* and hypoxia, 16 but is also present in anemia 4,1~ and hyperthyroidism.: 17,18 Myocardial oxygen consumption follows the same pattern. Although total myocardial oxygen consumption may increase in an enlarged heart by enough to raise the total body basal metabolic rate by 30 per eent, the oxygen consumption per 100 Gm. of left ventricle remains normal. 7 Whatever the mechanism may be, it is apparent that measurement of coronary flow by the nitrous oxide method leaves many questions about the coronary circulation unanswered. Newer techniques of flow measurement, such as those involving P~t-antipyrine, Kr, ~'~ Rb, ~6 and hydrogen, which also measure flow per unit
CORONARY FLOW
47
mass, give no indication of the magnitude of the total coronary circulation, and offer no advantage other than speed of performance. While all cf these methods will reflect acute changes, it is clear that some method for measuring total flow in the human patient is needed. Of even greater importance, particularly in eorGnary disease, is the need for some better method to evaluate coronary reserve. This may very well prove to be unrelated to the measurement of coronary flow itself, but instead be concerned more with metabolic events in the hypoxic cell. REACTIVITY OF CORONARY VESSELS
Most experimental studies of the coronary circulation have been concerned with the relationships between coronary flow and a variety of physiological events and nonphysiological interventions. A sensitive mechanism causing variations in flow through changes in coronary vascular resistance has been described. It is clear though, that this mechanism must have its limits TM and that a point must be reached when the arterioles are maximally or minimally dilated, when vascular resistance can no longer change, and when further alterations in flow by this mechanism can no longer be reasonably expected. When coronary flow to the left ventricle is reduced (fig. 1), coronary vascular resistance is seen to fall sharply from its peak values and to reach a minimum plateau. This plateau represents maximal arteriolar dilatation. The upper plateau of coronary vascular resistance probably represents maximal arteriolar constriction, since oxygen values are high at this point-evidence of overperfusion of the myocardium (fig. 2). Perfusion at aortic pressure (open circle) indicates that in normal situations, coronary vascular resistance is maintained midway between maximal constriction and maximal dilatation. The steep slGpe of the curve at this point demonstrates the sensitivity of response in either direction to an increased or decreased oxygen delivery. Evaluation of coronary dilator drugs must be undertaken when coronary vascular resistance is at the bottom of this curve, since a resistance fall that is not beyond that obtained by hypoxia alone will be meaningless in terms of therapeutic benefit. CORONARY INSUFFICIENCY
Coronary insufficiency is no longer a question of semantics. It has definite clinical, biochemical, and hemodynamie significance. When coronary blood flow to the left ventricle is reduced while maintaining a constant aortic pressure, 2~ a stage is reached where blood flow becomes inadequate for the needs of the myocardium (fig. 2). At this point, four things happen simultaneously: 1. Coronary vascular resistance falls to a minimum value, indicating maximal arteriolar dilation. 2. Coronary sinus oxygen content falls to a minimum value, indicating maximal extraction of oxygen by the myocardium. 3. Left ventricular failure occurs, as evidenced by a rise in left atrial pressure. 4. The normal pattern of lactate extraction by the myocardium ceases. Coronary sinus lactate exceeds that in the arterial blood, indicating
48
CASE AND BOVEN
2.5 CVR
2.0
1.5
1.0
0
OFF PUMP
0.5 CORONARY FLOW MI.,/MIN I
I
I
,
I
I
0 20 40 60 80 1oo Fig. 1.--Response of coronary vascular resistance (CVR) to variations in coronary flow. Note the plateau of maximal CVR at high flow, the zone of sharp fall in CVR indicating active arteriolar dilation in response to decreased oxygen concentration in the myoeardium, and the plateau of minimal CVR at low flow. Open circle represents perfusion at aortic pressure. the onset of partial anaerobic metabolism. This same sequence of events occurs if coronary flow is kept at a constant rate and aortic pressure is raised-a situation more analogous to clinical coronary insufficiency. While evidence of anaerobic metabolism was not noted in earlier studies of patients with coronary disease, this metabolic disturbance may be found in the greater proportion of such patients if exercise is severe enough) One of the limiting factors in cardiac performance under hypoxie conditions" appears to be the amount of energy that may be obtained in this fashion. Skeletal muscle will continue to work effectively under hypoxic conditions with the production of large quantities of lactate, but the myocardium is unable to derive more than a small amount of energy in this manner. 2~ The onset of left ventricular failure is clearly related to the marginal state of myocardial oxygenation, but whether this failure is the result of lactate accumulation in the heart is not known. Much of the evidence in the older studies of anaerobic myocardial metabolism indicates that lactate has a deleterious effect on myocardial contraction, 21 and that the su_rvivM of a
CORONARY F L O W
49
2.5 CVR
2.0
i.5 1.0
C.S.
!
I
15
02 10 CONTENT ML/100 ml 5
J I
LFFT
I
20 -
h___
ATRIAL PRESS. 15 MM Hg 10 -
o
'
4b
'6b
CORONARY FLOW ML/MIN
Fig. 2.--Events accompanying a reduction of coronary flow to the point of insufficiency. Coronary sinus (CS) oxygen content falls to a minimum value at the same time that CVR reaches a minimmn, left atrial (LA) pressure rises, and output of lactate by the myoeardium (not shown) begins. heart will be greatly prolonged if the accumulation of lactate in the myocardium during anaerobiasis can be reduced7 2 Regardless of the mechanism, left ventricular failure is part of the picture Of experimentally induced coronary insufficiency. This has also been demonstrated in human beings. Catheterization studies during angina induced by exercise show that left ventricular failure accompanies angina at all times. This was most extensively shown by Miiller and RCrvik, 23 who obtained a striking rise in pulmonary wedge pressure after exercise in a series of patients with coronary artery disease, anginal syndrome, and hearts of normal
50
CASE AND B.OVEN
size. At rest, the pulmonary wedge pressure was normal in all cases, but would double or triple during exercise, sometimes to values exceeding 30 mm Hg. Anginal pain was induced in most cases, but was not present unless there was also accompanying left ventrieular failure as evidenced by an abnormally elevated wedge pressure. Spontaneous attacks of angina during catheterization also were observed by Miiller and R~rvik, as well as by Johnson e t a l d 4 In each ease, the pattern was similar to that seen in induced angina, with a rise in pulmonary artery or wedge pressure associated with the pain, and a fall in pressures to normal with relief of angina. At this point, it might be suggested that anginal pain could in fact be due to the sudden elevation of left atrial and pulmonary artery pressures rather than to myocardial hypoxia itself. That this is not the ease is evident from exercise studies in left ventricular failure from other causes, as well as in mitral stenosis, in which equivalent pressure increases in the left atrium and pulmonary circuit occur without the occurrence of anginal pain. Miiller and R~rvik ~3 further noted that whereas a rise in pulmonary arterial and wedge pressure occurred within one minute after the start of exercise, chest pain did not begin until 3 to 5 minutes later. There are still many patients, however, who may describe their symptoms after exercise as partially pain and partially respiratory distress, and may truly be giving evidence of both left ventrieular failure and myocardial hypoxia. Nitroglycerine is unquestioned in its ability to relieve this syndrome of coronary insufficiency, but a clear understanding of its mode of action has thus far eluded us. Can nitroglycerine increase coronary flow to an isehemic segment distal to a narrowed coronary vessel? It has been tacitly assumed that nitroglycerine acts in this manner, primarily on the basis of studies involving the coronary arteriole in its normal partially constricted state. Even though nitroglycerine may be a potent coronary dilator under these circumstances, there is reason to believe it may exert little action on arterioles already subject to the strong stimulus of hypoxia. The widened major coronary vessels seen in coronary angiograms after administration of nitroglycerine are not evidence that coronary flow has increased, or that coronary vascular resistance has been reduced. They are evidence only of increased size of the observed segment and give no indication of either blood velocity Or arteriolar tone. Nitroglycerine has a profound effect on coronary circulation in the normal human subject, with measured flows increasing by more than 60 per cent. 25 Coronary sinus oxygen values are not above normal during this change, which indicates that myocardial oxygen consumption is increased by an equivalent amount, and that this drug is a "malignant" dilator in man, achieving its action solely as a consequence of its deleterious effect on oxygen consumption. It is difficult to picture a drug that markedly increases myocardial oxygen consumption and at the same time returns the electrocardiographic, biochemical, hemodynamie, and symptomatic picture of myocardial ischemia to normal. If we try to reconcile this paradox by postulating a dog-man
COnONARY FLOW
51
species difference, we will have to change our experimental techniques and re-evaluate much of what we think we know. Coronary flow actually falls in patients with severe coronary disease after administration of nitroglycerine} 6 and this fall is accompanied by an equivalent fall in aortic diastolic pressure. These findings are compatible with the concept of a fixed resistance responding only to change in perfusion pressure, and are in accord with the theoretical considerations presented. Persantin (dipyridamole), which is at least as good a coronary dilator as nitroglycerine, has no effect on angina. Some studies have demonstrated a nitroglycerine-like action for Persantin in man, 27 while others 2s have shown it to cause a rise in coronary sinus oxygen content--the characteristic of a true "benign" dilator. Even when the coronary sinus oxygen was so ihcreased, this drug, in contrast to nitroglycerine, did nothing to improve the exercise tolerance in anginal patients. The finding of left ventrieular failure during myocardial ischemia did lead to studies that throw some light on the otherwise mysterious action of nitroglycerine. Johnson and associates 24 give ample evidence that it is an effective agent in the treatment of left ventrieular failure when coronary insufficiency is not present, by demonstrating a fall in elevated pulmonary arterial and wedge pressures associated with a relief of symptoms. They concluded that nitroglycerine was an effective drug for routine clinical use in this state, and attributed its action to venous pooling. Similarly, Sarnoff and Sarnoff29 showed that only slight systemic vasodilatation often caused a striking reduction in pulmonary vascular pressures when these were initially high. Gorlin and associates} T M in studying the hemodynamie effects of nitroglycerine, also found a striking fall in the pulmonary wedge pressure of normal subjects as well as in patients with coronary disease and with left ventrieular overwork, with a decrease averaging 30 per cent, 33 per cent, and 57 per cent respectively. Although cardiac output also decreased significantly, peripheral vascular resistance was unchanged, which suggests again that a venous pooling mechanism may have been responsible for these changes. Thus, it may be postulated that nitroglycerine exerts its beneficial action in angina merely by relief of the accompanying failure. This sequence of events is certainly present in the eases observed by Johnson, and by Miiller and R~rvik. However, it seems more reasonable to assume that nitroglycerine acts in two ways: (1) by reduction of myocardial oxygen requirements, which in itself may transform a segment of heart muscle which is only marginally oxygenated into one that is adequately perfused. A venous pooling effect could achieve this by both lowering arterial pressure and decreasing heart size; (2) by promptly treating the failure itself by the same mechanism. The mode of action of nitroglycerine certainly remains controversial, but our thinking appears to be moving nearer to the reasoning of Brunton, 3~ who introduced nitrites in 1867 for the relief of angina by reduction of arterial pressure. If this is the mechanism of action, reduction of myocardial oxygen consumption by an equivalent amount by another means should be just as
52
CASE AND ROVEN
effective. Indeed, a reduction in heart rate by carotid sinus massage often brings prompt relief, although this observation is somewhat vitiated by its association with a presumed reflex mechanism. REFLEX MECHANISMS
The association of cold weather and increased severity of the anginal syndrome was well appreciated by the older clinicians. Keeping the feet warm with woolen socks and the use of bed warmers were considered basic prophylactic measures. Not only was the avoidance of exposure to cold appreciated, but the beneficial effects of local heat were also well known. The application of a hot water bottle to the chest was a common and apparently effective way of coping with an acute anginal attack. 31 In 1944, Freedberg and associates z2 reported the effects of local heat and cold in patients with angina pectoris. It had already been established by Riseman and Stern ~ that almost all patients with angina would feel pain with exercise in a cold room while many would remain symptom free with similar or more intense exercise at normal room temperature. Freedberg studied 22 patients with angina pectoris by comparing the response to a standard exercise test after local applications of heat and cold, and after the administration of nitroglycerine. The application of ice to the hand, or chilling the skin of the thigh or back, produced a striking decrease in exercise tolerance. This effect could not be prevented by obliteration of the venous return from the cold hand, thus excluding the possible effect of cooling the blood. Most interestingly, immersion of the hand in warm water, or the prior application of heat to the abdomen, markedly increased the amount of exercise that could be performed before the onset of anginal pain. Both the administration of nitroglycerine and the prior application of local heat were of equal value in increasing exercise tolerance, and were of benefit to the same patients. Freedberg concluded from these studies that local cGld precipitates angina by means of some reflex mechanism, and that local heat similarly affords protection. He further noted that these effects were not consistently related to either heart rate or blood pressure. Recently, Murray :~4 has demonstrated in dogs that breathing air at - 1 0 ~ F., without bodily exposure to cold, can cause a 5 ~ F. fall in left atrial temperature. In studying 12 patients with angina and normal resting electrocardiograms, he noted that breathing cold air in a similar manner precipitated angina in 5 patients and caused S-T depressions in all, and concluded that these changes were due to cooling of pulmonary blood or to generalized vasoconstriction. Unfortunately, the author did not report measurements of arterial pressure and heart rate, thus making it difficult to evaluate these resuits in terms of the known determinants of oxygen consumption. The cooling of pulmonary blood, however, raises some interesting questions in view of the known dependence of the hemoglobin dissociation curve on temperature. This leftward shift at lower temperatures makes less oxygen available to the tissues at a given oxygen saturation. It would seem reasonable that in a heart with a marginal oxygen supply, this could very well~ lower myocardial pO2 enough to cause hypoxic symptoms.
CORONARY FLOW
53
The beneficial effect of local heat is most provocative, and remains to be more fully studied. It certainly appears to involve a reflex mechanism, but whether it acts directly as a coronary dilator, or causes venous pooling through a generalized dilating action, is not known. Conceivably, it could interfere with the catecholamine-releasing response to stress proposed by Raab et al. 35 This latter response may well be the neurohumoral mechanism to explain all of Freedberg's findings. Additional support for this explanation comes from Arnett's and Watts 'a6 finding of irmcreased levels of catecholamines in the urine of men exposed to cold. The concept that epinephrine could be the mediator between stress and angina was proposed by Raab 26 years ago. He has since postulated what he calls a specific "oxygen-wasting" effect of the catecholamines on the myocardium. Over the years, he has continued to accumulate evidence and to reinforce his conviction that these hormones have a specific myocardial metabolic effect that can cause hypoxia in those areas of the heart that are marginally perfused. While most of the evidence is speculative, the reasoning is logical and intriguing. It is known that catecholamines are increased in cardiac muscle and in blood after stress, as they are after the administration of nicotineY However, the central point in this thesis still remains to be proved, namely that the catecholamines cause a utilization of oxygen by the myocardium out of proportion to that resulting from any hemodynamic alterations that accompany the hormone release. In recent experiments designed to separate the effects of catecholamines from those of increased heart work, Raab demonstrated that in cats with narrowed coronary vessels, the heart could tolerate significant increases in rate or pressure without accompanying S-T changes. 35 After injection of epinephrine or sympathetic stimulation, marked S-T changes were apparent, although the accompanying heart rate and pressure changes were not greater than those obtained previously. Unfortunately, Raab has equated these electrocardiographic changes to the state of myocardial oxygenation. Actually, the demonstration by Sayen, 8s that myocardial pO2 rises under these circumstances, would seem to rule out the "oxygen-wasting" propensity of catecholamines. On the other hand, the finding of increased oxygen together with excess lactate in coronary sinus blood after administration of catecholamines 9 suggests that the heart may not be able to make use of the excess oxygen that seems to be present. The view that this is due to localized hypoxia caused by stagnation of blood associated with high intracardiac pressures has by no means been proved. Not all physicians subscribe to Raab's belief that anginal patients should be treated by irradiation of the adrenals, but there is no question that the whole subject of reflex mechanisms and the role of cateeholamines deserves further study, REFERENCES
1. Messer, J. V., and Neill, W. A.: The oxygen supply of the human heart. Am. J. Cardiol. 9:384, 1962. 2. Case, R. B., Berglund, E., and Sarnoff,
S. J.: Ventricular function. VII. Changes in coronary resistance and ventricular function resulting from acutely induced anemia and the el-
54 fect thereon of coronary stenosis. Am. J. Med. 18:397, 1955. 3. Messer, J. V., Wagman, R. J., Levine, H. J., Neill, W. A., Krasnow, N., and Gorlin, R.: Patterns of human myocardial oxygen extraction during rest and exercise. J. Clin. Invest. 41:725, 1962. 4. Lombardo, T. A., Rose, L., Taeschler, M., Tuluy, S., and Bing, R. J.: The effect of exercise on coronary blood flow, myocardial oxygen consmnption, and cardiac efficiency in man. Circulation 7:71, 1953. 5, Sarnoff, S. J,, Braunwald, E., Welch, G. H., Case, R. B., Stainsby, W. N., and Maeruz, R.: Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension-time index. Am. J. Physiol. 192:148, 1958. 6. Katz, L. N.: The performance of the heart. Circulation 21:483, 1960. 7. Levine, H. J., and Wagman, R. J.: Energetics of the human heart. Am. J. Cardiol. 9:372, 1962. 8. Case, R. B., Berglund, E., and Sarnoff, S. J.: Ventrieular function. II. Quantitative relationship between coronary flow and ventricular function, with observations on unilateral failure. Circulation 2:319, 1954. 9. Krasnow, N., Hood, W. B., Jr., Rolett, E. L., and Yurchak, P. M.: Diagnostic significance of myocardial anaerobiasis. Circulation 26:745, 1962. 10. Bing, R. J.: The coronary circulation in health and disease as studied by coronary sinus catheterization. Bull. New York Acad. Med. 27:405, 1951. 11. Braehfeld, N., Bozer, J., and Gorlin, R.: Action of nitroglycerine on the coronary circulation in normal and mild cardiac subjects. Circulation 19:697, 1959. 12. Danforth, W. H., Ballard, F. B., Kako, K., Choudhury, J. D., and Bing, R. J.: Metabolism of the heart in failure. Circulation 2I: 112, 1960. 13. Regan, T. J., Talmers, F. N., Christensen, R. C., Wada, T., and Hellems, H. K.: Coronary blood //ow and myocardial metabolism in aortic insuffleieney. Circulation 14:987, 1956. 14. Rowe; G. G., Castillo, C. A., Maxwell,
CASE AND ROVEN G. M., and Crumpton, C. W.: A hemodynamic study of hypertension including observations on coronary blood flow. Ann, Int. Med. 54:405, 1961. 15. Rowe, G. G., Maxwell, G. M., Castillo, G. A., Huston, J. H., and Crumpton, C. W.: Hemodyamnics of mitral stenosis with special reference to coronary blood flow and myocardial oygen consumption. Circulation 22: 559, 1960... 16. Hellems, H. K., Ord, J. W., Talmers, F. N., and Christensen, R. C.: Effect of hypoxia on coronary blood flow and myocardial metabolism in normal human subjects. Coreulation 16:893, 1957. 17. Leight, L., DeFazio, V., Talmers, F. T., Regan, T. J., and Hellems, H. K.: Coronary blood flow, myocardial oxygen consumption and myocardial metabolism in normal and hyperthyroid human subjects. Circulation 14:90, 1956. 18. Rowe, G. G., Huston, J. H., Weinstein, A. B., Tuchman, H., Brown, J. F., and Crumpton, C. W.: The hemodynamics of thyrotoxicosis in man with special reference to coronary blood flow and myocardial oxygen consumption. J. Clin. Invest. 35:272, 1956. 19. Case, R. B., Griggs, D. M., Jr., and Pierson, R. N., Jr.: Determinations of the limit of reactivity of the coronary vascular bed. Circulation 22:731, 1960. 20. Shea, T. M., Watson, R. M., Piotrowski, S. F., Dermksian, G., and Case, R. B.: Anaerobic myocardial metabolism. Am. J. Physiol. 203:463, 1962. 21. Clark, A. J., Gaddie, R., and Stewart, C. P.: The anaerobic activity of the isolated frog's heart. J. Physiol. 75: 321, 1932. 22. Tennant, R.: Factors concerned in the arrest of contraction in an ischemie myocardial area. Am. J. Physiol. 113: 677, 1935. 23. Miiller, O., and R~rvik, K.: Haemodynamic consequences of coronary heart disease. Brit. Heart J. 20:302, 1958. 24. Johnson, J. B., Fairley, A., Carter, C.: Effects of sublingual nitroglycerine
CORONARY FLOW
25.
26.
27.
28.
29.
30. 31.
on pulmonary arterial pressure in patients with left ventricular failure. Ann, Int. Med. 50:34, 1959. Brachfeld, N., Bozer, J., and Gorlin, R.: Action of nitroglycerine on the coronary circulation in normal and mild cardiac subjects. Circulation 19: 697, 1959, Gorlin, R., Brachfeld, N., MacLeod, C., and Bopp, P.: Effect of nitroglycyerine on the coronary circulation in patients with coronary artery disease or increased left ventricnlar work. Circulation 19.:705, 1959. Wendt, V. E., Sundermeyer, J. F., den Bakker, P. B., and Bing, R. J.: The relationship between coronary blood flow, myocardial oxygen consumption and cardiac work as influenced by persantin. Am. J. Cardiol. 9:449, 1962. Kinsella, D., Troup, W., and McGregor, M.: Studies with a new coronary vasodilator drug: Persantin. Am. Heart J. 63:146, 1962. Sarnoff, S. J., and Sarnoff, L. C.: Neurohemodynamies of puhnonary edema. II. The role of sympathetic pathways in the elevation of pulmonary and systemic vascular pressures following the intracisternal injection of fibrin. Circulation 6:51, 1952. Brunton, T. L.: On the use of nitrite of amyl. Lancet 2:97, 1867. Robinson, B.: Angina pectoris. Am. J. M. So. 123:225, 1902.
55 32. Freedberg, A. S., Spiegl, E. D., and Riseman, J. E. F.: Effect of external heat and cold on patients with angina pectoris: Evidence for the existence of a reflex factor. Am. Heart J. 27:611, 1944. 33. Riseman, J. E. F., and Stern, B.: A standardized exercise tolerance test for patients with angina pectoris on exertion. Am. J. M. Sc. 188:646, 1934. 34. Murray, M. J.: Effect of inspiration of cold air on electrocardiograms of normal humans with angina pectoris. Circulation 26:765, 1962. 35. Raab, W., Van Lith, P., Lepeschkin, E., and Herrlieh, H. C.: Catecholamineinduced myocardial hypoxia in the presence of impaired coronary dilatability independent of external cardiac work. Am. J. Cardiol. 9:455, 1962. 36. Arnett, E. L., and Watts, D. T.: Cateeholamine excretion in men exposed to cold. J. Applied Physiol. 15:499, 1960. 37. Raab, W.: Key position of catecholamines in functional and degenerative cardiovascular pathology, Am. J. Cardiol 5:571, 1960. 38. Sayen, Ji J., Kateher, A. H., Sheldon, W. F., and Gilbert, C. M.: The effect of levarterenol on polarographic myocardial oxygen, the epicardial electrocardiogram and contraction in nonischemic dog hearts, and experimental acute regional ischemia. Circulation 8:109, 1960.
Robert B. Case, M.D., Director, Laboratory of- Experimental Cardiology, and Associate Attending Physician, St. Luke's Hospital, New York City; Instructor in Medicine, Columbia University Medical College, New York City. Robert B. Roven, M.D., Postdoctoral Research Fellow, Nation Heart Institute, New York City.
CASE AND ROBERT B. ROVEN
N THE SURFACE it seems illogical that a person with severely diseased coronary vessels should have a normal Coronary flow/ On further consideration, however, this should not surprise us greatly, since all evidence points to the subservience of flow to the oxygen needs of the myocardium, and the factors which govern this--even in severe coronary sclerosis--are unchanged.
O
RELATION BETWEEN CORONARYFLOW AND MYOCARDIALOXYGEN CONSUMPTION
D~erminants of Coronary Flow It is only recently that the fundamental determinants of coronary flow have been appreciated. Correlation had been attempted with such factors as cardiac output, mechanical work, myocardial oxygen consumption, aortic pressure, diastolic time, heart size, arterial oxygen content, and a host of other variables. The finding that appears to unify these seemingly diverse and tenu, ously connected variables is that coronary sinus oxygen content 2-4 remains the same regardless of the heart's physiological state, indicating that coronary flow is adjusted to maintain a constant myocardial oxygen value. A constant arteriovenous difference inevitably results in such a system, and hence it should be evident that alterations in coronary flow and myocardial oxygen consumption must proceed in a parallel manner. Changes in coronary flow thus reflect only changes in myocardial oxygen consumption. This system is exquisitely sensitive, reacting promptly to any intervention that may vary the oxygen concentration of the myocardial cell. It can be upset only by substances acting independently on the coronary bed, or by requiring of it responses that exceed its limits of reactivity. Determinant~ of Myo,cardial Oxygen Consumption The determinants of myocardial oxygen consumption itself have recently been clarified. In the past it was reasonably assumed that the work performed by the ventricle was closely related to the oxygen consumed, and this work was calculated in the strict physical sense as the integral of pressure and flow or, more simply, as the product of pressure and flow. Separation of these two factors in isolated heart experiments~,6 yielded the surprising result that myocardial oxygen consumption depended solely upon pressure generated by the ventricle and its frequency of so doing, and that oxygen consumption was unaffected by alterations in cardiac output. Thus, mechanical efficiency of the ventricle, calculated in the traditional manner, may vary greatly with changes in cardiac output. While data in the human being are not so complete, these findings appear to b e confirmed by From the Department of Medicine, St. Lukes Hospital, New York City. 45 PaOGR~SSIN CA~mOVASCVLAJaDISEASES,VOL. 6, No. 1 (JULY), 1963
46
CASE A N D ROVEN
the additional observation that oxygen consumption is also related to cardiac diameter. 7 A consideration of these factors together indicates that the determining factor in oxygen consumption, and thus in coronary flow, is the tension of the myocardial fiber created per unit of time, and that this may be elinieally estimated by observation of the cardiac rate and size, and the systolic pressure. Logically then, in a patient with coronary disease, there would be no reason to suspect a reduction in coronary flow unless these determinants of oxygen consumption were also reduced. Regarded from another view, it has been shown that when coronary flow is experimentally lowered, a fall in arterial pressure occurs until oxygen supply and demand are again in accord, s Not only is resting coronary flow normal in coronary disease, but patients so aflqieted also respond to exercise with an increase in flow equivalent to that in normal persons. Hence, flow measurements give no indication whatsoever of the degree of coronary patency or the accompanying marginal state of myocardial oxygenation. The best index of functional incompetence of the coronary vessels seems to lie in certain responses to stress. Coronary sinus blood usually shows both a fall in oxygen content with exercise, 3 which indicates exhaustion of the arteriolar dilating reserve, and the production of excess lactate, 9 which means that the heart is beginning to satisfy some of its energy requirements through anaerobic metabolism. The onset of angina, or changes in the S-T segment of the electrocardiogram after stress, also suggest inadequacy of the coronary dilatory reserve, although these responses are subiect to many other influences. It is also interesting to note that in other disease states, the measurement of coronary flow is of little value in assessing the adequacy of the coronary eirctdation, the severity of the disease, or even the diagnosis. In cardiac failure, ventrieular hypertrophy, coronary artery disease, hypertension, mitral stenosis, aortic insufficiency, and aortic stenosis the coronary flow, as determined by the nitrous oxide technique, is almost always within the normal rangeA 1~ It must be remembered that the nitrous oxide method, which has been used in nearly all human studies, is only capable of measuring flow per 100 Gin. of left ventricle; actual total flow in an enlarged heart may be many times normal. The reasons for this seeming "normalization" of coronary flow per unit mass are not clear, but it is evident that myocardial hypertrophy proportional to the increased total ecronary flow must occur. An increase in flow per unit of muscle mass has been seen only in such acute situations as exercise* and hypoxia, 16 but is also present in anemia 4,1~ and hyperthyroidism.: 17,18 Myocardial oxygen consumption follows the same pattern. Although total myocardial oxygen consumption may increase in an enlarged heart by enough to raise the total body basal metabolic rate by 30 per eent, the oxygen consumption per 100 Gm. of left ventricle remains normal. 7 Whatever the mechanism may be, it is apparent that measurement of coronary flow by the nitrous oxide method leaves many questions about the coronary circulation unanswered. Newer techniques of flow measurement, such as those involving P~t-antipyrine, Kr, ~'~ Rb, ~6 and hydrogen, which also measure flow per unit
CORONARY FLOW
47
mass, give no indication of the magnitude of the total coronary circulation, and offer no advantage other than speed of performance. While all cf these methods will reflect acute changes, it is clear that some method for measuring total flow in the human patient is needed. Of even greater importance, particularly in eorGnary disease, is the need for some better method to evaluate coronary reserve. This may very well prove to be unrelated to the measurement of coronary flow itself, but instead be concerned more with metabolic events in the hypoxic cell. REACTIVITY OF CORONARY VESSELS
Most experimental studies of the coronary circulation have been concerned with the relationships between coronary flow and a variety of physiological events and nonphysiological interventions. A sensitive mechanism causing variations in flow through changes in coronary vascular resistance has been described. It is clear though, that this mechanism must have its limits TM and that a point must be reached when the arterioles are maximally or minimally dilated, when vascular resistance can no longer change, and when further alterations in flow by this mechanism can no longer be reasonably expected. When coronary flow to the left ventricle is reduced (fig. 1), coronary vascular resistance is seen to fall sharply from its peak values and to reach a minimum plateau. This plateau represents maximal arteriolar dilatation. The upper plateau of coronary vascular resistance probably represents maximal arteriolar constriction, since oxygen values are high at this point-evidence of overperfusion of the myocardium (fig. 2). Perfusion at aortic pressure (open circle) indicates that in normal situations, coronary vascular resistance is maintained midway between maximal constriction and maximal dilatation. The steep slGpe of the curve at this point demonstrates the sensitivity of response in either direction to an increased or decreased oxygen delivery. Evaluation of coronary dilator drugs must be undertaken when coronary vascular resistance is at the bottom of this curve, since a resistance fall that is not beyond that obtained by hypoxia alone will be meaningless in terms of therapeutic benefit. CORONARY INSUFFICIENCY
Coronary insufficiency is no longer a question of semantics. It has definite clinical, biochemical, and hemodynamie significance. When coronary blood flow to the left ventricle is reduced while maintaining a constant aortic pressure, 2~ a stage is reached where blood flow becomes inadequate for the needs of the myocardium (fig. 2). At this point, four things happen simultaneously: 1. Coronary vascular resistance falls to a minimum value, indicating maximal arteriolar dilation. 2. Coronary sinus oxygen content falls to a minimum value, indicating maximal extraction of oxygen by the myocardium. 3. Left ventricular failure occurs, as evidenced by a rise in left atrial pressure. 4. The normal pattern of lactate extraction by the myocardium ceases. Coronary sinus lactate exceeds that in the arterial blood, indicating
48
CASE AND BOVEN
2.5 CVR
2.0
1.5
1.0
0
OFF PUMP
0.5 CORONARY FLOW MI.,/MIN I
I
I
,
I
I
0 20 40 60 80 1oo Fig. 1.--Response of coronary vascular resistance (CVR) to variations in coronary flow. Note the plateau of maximal CVR at high flow, the zone of sharp fall in CVR indicating active arteriolar dilation in response to decreased oxygen concentration in the myoeardium, and the plateau of minimal CVR at low flow. Open circle represents perfusion at aortic pressure. the onset of partial anaerobic metabolism. This same sequence of events occurs if coronary flow is kept at a constant rate and aortic pressure is raised-a situation more analogous to clinical coronary insufficiency. While evidence of anaerobic metabolism was not noted in earlier studies of patients with coronary disease, this metabolic disturbance may be found in the greater proportion of such patients if exercise is severe enough) One of the limiting factors in cardiac performance under hypoxie conditions" appears to be the amount of energy that may be obtained in this fashion. Skeletal muscle will continue to work effectively under hypoxic conditions with the production of large quantities of lactate, but the myocardium is unable to derive more than a small amount of energy in this manner. 2~ The onset of left ventricular failure is clearly related to the marginal state of myocardial oxygenation, but whether this failure is the result of lactate accumulation in the heart is not known. Much of the evidence in the older studies of anaerobic myocardial metabolism indicates that lactate has a deleterious effect on myocardial contraction, 21 and that the su_rvivM of a
CORONARY F L O W
49
2.5 CVR
2.0
i.5 1.0
C.S.
!
I
15
02 10 CONTENT ML/100 ml 5
J I
LFFT
I
20 -
h___
ATRIAL PRESS. 15 MM Hg 10 -
o
'
4b
'6b
CORONARY FLOW ML/MIN
Fig. 2.--Events accompanying a reduction of coronary flow to the point of insufficiency. Coronary sinus (CS) oxygen content falls to a minimum value at the same time that CVR reaches a minimmn, left atrial (LA) pressure rises, and output of lactate by the myoeardium (not shown) begins. heart will be greatly prolonged if the accumulation of lactate in the myocardium during anaerobiasis can be reduced7 2 Regardless of the mechanism, left ventricular failure is part of the picture Of experimentally induced coronary insufficiency. This has also been demonstrated in human beings. Catheterization studies during angina induced by exercise show that left ventricular failure accompanies angina at all times. This was most extensively shown by Miiller and RCrvik, 23 who obtained a striking rise in pulmonary wedge pressure after exercise in a series of patients with coronary artery disease, anginal syndrome, and hearts of normal
50
CASE AND B.OVEN
size. At rest, the pulmonary wedge pressure was normal in all cases, but would double or triple during exercise, sometimes to values exceeding 30 mm Hg. Anginal pain was induced in most cases, but was not present unless there was also accompanying left ventrieular failure as evidenced by an abnormally elevated wedge pressure. Spontaneous attacks of angina during catheterization also were observed by Miiller and R~rvik, as well as by Johnson e t a l d 4 In each ease, the pattern was similar to that seen in induced angina, with a rise in pulmonary artery or wedge pressure associated with the pain, and a fall in pressures to normal with relief of angina. At this point, it might be suggested that anginal pain could in fact be due to the sudden elevation of left atrial and pulmonary artery pressures rather than to myocardial hypoxia itself. That this is not the ease is evident from exercise studies in left ventricular failure from other causes, as well as in mitral stenosis, in which equivalent pressure increases in the left atrium and pulmonary circuit occur without the occurrence of anginal pain. Miiller and R~rvik ~3 further noted that whereas a rise in pulmonary arterial and wedge pressure occurred within one minute after the start of exercise, chest pain did not begin until 3 to 5 minutes later. There are still many patients, however, who may describe their symptoms after exercise as partially pain and partially respiratory distress, and may truly be giving evidence of both left ventrieular failure and myocardial hypoxia. Nitroglycerine is unquestioned in its ability to relieve this syndrome of coronary insufficiency, but a clear understanding of its mode of action has thus far eluded us. Can nitroglycerine increase coronary flow to an isehemic segment distal to a narrowed coronary vessel? It has been tacitly assumed that nitroglycerine acts in this manner, primarily on the basis of studies involving the coronary arteriole in its normal partially constricted state. Even though nitroglycerine may be a potent coronary dilator under these circumstances, there is reason to believe it may exert little action on arterioles already subject to the strong stimulus of hypoxia. The widened major coronary vessels seen in coronary angiograms after administration of nitroglycerine are not evidence that coronary flow has increased, or that coronary vascular resistance has been reduced. They are evidence only of increased size of the observed segment and give no indication of either blood velocity Or arteriolar tone. Nitroglycerine has a profound effect on coronary circulation in the normal human subject, with measured flows increasing by more than 60 per cent. 25 Coronary sinus oxygen values are not above normal during this change, which indicates that myocardial oxygen consumption is increased by an equivalent amount, and that this drug is a "malignant" dilator in man, achieving its action solely as a consequence of its deleterious effect on oxygen consumption. It is difficult to picture a drug that markedly increases myocardial oxygen consumption and at the same time returns the electrocardiographic, biochemical, hemodynamie, and symptomatic picture of myocardial ischemia to normal. If we try to reconcile this paradox by postulating a dog-man
COnONARY FLOW
51
species difference, we will have to change our experimental techniques and re-evaluate much of what we think we know. Coronary flow actually falls in patients with severe coronary disease after administration of nitroglycerine} 6 and this fall is accompanied by an equivalent fall in aortic diastolic pressure. These findings are compatible with the concept of a fixed resistance responding only to change in perfusion pressure, and are in accord with the theoretical considerations presented. Persantin (dipyridamole), which is at least as good a coronary dilator as nitroglycerine, has no effect on angina. Some studies have demonstrated a nitroglycerine-like action for Persantin in man, 27 while others 2s have shown it to cause a rise in coronary sinus oxygen content--the characteristic of a true "benign" dilator. Even when the coronary sinus oxygen was so ihcreased, this drug, in contrast to nitroglycerine, did nothing to improve the exercise tolerance in anginal patients. The finding of left ventrieular failure during myocardial ischemia did lead to studies that throw some light on the otherwise mysterious action of nitroglycerine. Johnson and associates 24 give ample evidence that it is an effective agent in the treatment of left ventrieular failure when coronary insufficiency is not present, by demonstrating a fall in elevated pulmonary arterial and wedge pressures associated with a relief of symptoms. They concluded that nitroglycerine was an effective drug for routine clinical use in this state, and attributed its action to venous pooling. Similarly, Sarnoff and Sarnoff29 showed that only slight systemic vasodilatation often caused a striking reduction in pulmonary vascular pressures when these were initially high. Gorlin and associates} T M in studying the hemodynamie effects of nitroglycerine, also found a striking fall in the pulmonary wedge pressure of normal subjects as well as in patients with coronary disease and with left ventrieular overwork, with a decrease averaging 30 per cent, 33 per cent, and 57 per cent respectively. Although cardiac output also decreased significantly, peripheral vascular resistance was unchanged, which suggests again that a venous pooling mechanism may have been responsible for these changes. Thus, it may be postulated that nitroglycerine exerts its beneficial action in angina merely by relief of the accompanying failure. This sequence of events is certainly present in the eases observed by Johnson, and by Miiller and R~rvik. However, it seems more reasonable to assume that nitroglycerine acts in two ways: (1) by reduction of myocardial oxygen requirements, which in itself may transform a segment of heart muscle which is only marginally oxygenated into one that is adequately perfused. A venous pooling effect could achieve this by both lowering arterial pressure and decreasing heart size; (2) by promptly treating the failure itself by the same mechanism. The mode of action of nitroglycerine certainly remains controversial, but our thinking appears to be moving nearer to the reasoning of Brunton, 3~ who introduced nitrites in 1867 for the relief of angina by reduction of arterial pressure. If this is the mechanism of action, reduction of myocardial oxygen consumption by an equivalent amount by another means should be just as
52
CASE AND ROVEN
effective. Indeed, a reduction in heart rate by carotid sinus massage often brings prompt relief, although this observation is somewhat vitiated by its association with a presumed reflex mechanism. REFLEX MECHANISMS
The association of cold weather and increased severity of the anginal syndrome was well appreciated by the older clinicians. Keeping the feet warm with woolen socks and the use of bed warmers were considered basic prophylactic measures. Not only was the avoidance of exposure to cold appreciated, but the beneficial effects of local heat were also well known. The application of a hot water bottle to the chest was a common and apparently effective way of coping with an acute anginal attack. 31 In 1944, Freedberg and associates z2 reported the effects of local heat and cold in patients with angina pectoris. It had already been established by Riseman and Stern ~ that almost all patients with angina would feel pain with exercise in a cold room while many would remain symptom free with similar or more intense exercise at normal room temperature. Freedberg studied 22 patients with angina pectoris by comparing the response to a standard exercise test after local applications of heat and cold, and after the administration of nitroglycerine. The application of ice to the hand, or chilling the skin of the thigh or back, produced a striking decrease in exercise tolerance. This effect could not be prevented by obliteration of the venous return from the cold hand, thus excluding the possible effect of cooling the blood. Most interestingly, immersion of the hand in warm water, or the prior application of heat to the abdomen, markedly increased the amount of exercise that could be performed before the onset of anginal pain. Both the administration of nitroglycerine and the prior application of local heat were of equal value in increasing exercise tolerance, and were of benefit to the same patients. Freedberg concluded from these studies that local cGld precipitates angina by means of some reflex mechanism, and that local heat similarly affords protection. He further noted that these effects were not consistently related to either heart rate or blood pressure. Recently, Murray :~4 has demonstrated in dogs that breathing air at - 1 0 ~ F., without bodily exposure to cold, can cause a 5 ~ F. fall in left atrial temperature. In studying 12 patients with angina and normal resting electrocardiograms, he noted that breathing cold air in a similar manner precipitated angina in 5 patients and caused S-T depressions in all, and concluded that these changes were due to cooling of pulmonary blood or to generalized vasoconstriction. Unfortunately, the author did not report measurements of arterial pressure and heart rate, thus making it difficult to evaluate these resuits in terms of the known determinants of oxygen consumption. The cooling of pulmonary blood, however, raises some interesting questions in view of the known dependence of the hemoglobin dissociation curve on temperature. This leftward shift at lower temperatures makes less oxygen available to the tissues at a given oxygen saturation. It would seem reasonable that in a heart with a marginal oxygen supply, this could very well~ lower myocardial pO2 enough to cause hypoxic symptoms.
CORONARY FLOW
53
The beneficial effect of local heat is most provocative, and remains to be more fully studied. It certainly appears to involve a reflex mechanism, but whether it acts directly as a coronary dilator, or causes venous pooling through a generalized dilating action, is not known. Conceivably, it could interfere with the catecholamine-releasing response to stress proposed by Raab et al. 35 This latter response may well be the neurohumoral mechanism to explain all of Freedberg's findings. Additional support for this explanation comes from Arnett's and Watts 'a6 finding of irmcreased levels of catecholamines in the urine of men exposed to cold. The concept that epinephrine could be the mediator between stress and angina was proposed by Raab 26 years ago. He has since postulated what he calls a specific "oxygen-wasting" effect of the catecholamines on the myocardium. Over the years, he has continued to accumulate evidence and to reinforce his conviction that these hormones have a specific myocardial metabolic effect that can cause hypoxia in those areas of the heart that are marginally perfused. While most of the evidence is speculative, the reasoning is logical and intriguing. It is known that catecholamines are increased in cardiac muscle and in blood after stress, as they are after the administration of nicotineY However, the central point in this thesis still remains to be proved, namely that the catecholamines cause a utilization of oxygen by the myocardium out of proportion to that resulting from any hemodynamic alterations that accompany the hormone release. In recent experiments designed to separate the effects of catecholamines from those of increased heart work, Raab demonstrated that in cats with narrowed coronary vessels, the heart could tolerate significant increases in rate or pressure without accompanying S-T changes. 35 After injection of epinephrine or sympathetic stimulation, marked S-T changes were apparent, although the accompanying heart rate and pressure changes were not greater than those obtained previously. Unfortunately, Raab has equated these electrocardiographic changes to the state of myocardial oxygenation. Actually, the demonstration by Sayen, 8s that myocardial pO2 rises under these circumstances, would seem to rule out the "oxygen-wasting" propensity of catecholamines. On the other hand, the finding of increased oxygen together with excess lactate in coronary sinus blood after administration of catecholamines 9 suggests that the heart may not be able to make use of the excess oxygen that seems to be present. The view that this is due to localized hypoxia caused by stagnation of blood associated with high intracardiac pressures has by no means been proved. Not all physicians subscribe to Raab's belief that anginal patients should be treated by irradiation of the adrenals, but there is no question that the whole subject of reflex mechanisms and the role of cateeholamines deserves further study, REFERENCES
1. Messer, J. V., and Neill, W. A.: The oxygen supply of the human heart. Am. J. Cardiol. 9:384, 1962. 2. Case, R. B., Berglund, E., and Sarnoff,
S. J.: Ventricular function. VII. Changes in coronary resistance and ventricular function resulting from acutely induced anemia and the el-
54 fect thereon of coronary stenosis. Am. J. Med. 18:397, 1955. 3. Messer, J. V., Wagman, R. J., Levine, H. J., Neill, W. A., Krasnow, N., and Gorlin, R.: Patterns of human myocardial oxygen extraction during rest and exercise. J. Clin. Invest. 41:725, 1962. 4. Lombardo, T. A., Rose, L., Taeschler, M., Tuluy, S., and Bing, R. J.: The effect of exercise on coronary blood flow, myocardial oxygen consmnption, and cardiac efficiency in man. Circulation 7:71, 1953. 5, Sarnoff, S. J,, Braunwald, E., Welch, G. H., Case, R. B., Stainsby, W. N., and Maeruz, R.: Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension-time index. Am. J. Physiol. 192:148, 1958. 6. Katz, L. N.: The performance of the heart. Circulation 21:483, 1960. 7. Levine, H. J., and Wagman, R. J.: Energetics of the human heart. Am. J. Cardiol. 9:372, 1962. 8. Case, R. B., Berglund, E., and Sarnoff, S. J.: Ventrieular function. II. Quantitative relationship between coronary flow and ventricular function, with observations on unilateral failure. Circulation 2:319, 1954. 9. Krasnow, N., Hood, W. B., Jr., Rolett, E. L., and Yurchak, P. M.: Diagnostic significance of myocardial anaerobiasis. Circulation 26:745, 1962. 10. Bing, R. J.: The coronary circulation in health and disease as studied by coronary sinus catheterization. Bull. New York Acad. Med. 27:405, 1951. 11. Braehfeld, N., Bozer, J., and Gorlin, R.: Action of nitroglycerine on the coronary circulation in normal and mild cardiac subjects. Circulation 19:697, 1959. 12. Danforth, W. H., Ballard, F. B., Kako, K., Choudhury, J. D., and Bing, R. J.: Metabolism of the heart in failure. Circulation 2I: 112, 1960. 13. Regan, T. J., Talmers, F. N., Christensen, R. C., Wada, T., and Hellems, H. K.: Coronary blood //ow and myocardial metabolism in aortic insuffleieney. Circulation 14:987, 1956. 14. Rowe; G. G., Castillo, C. A., Maxwell,
CASE AND ROVEN G. M., and Crumpton, C. W.: A hemodynamic study of hypertension including observations on coronary blood flow. Ann, Int. Med. 54:405, 1961. 15. Rowe, G. G., Maxwell, G. M., Castillo, G. A., Huston, J. H., and Crumpton, C. W.: Hemodyamnics of mitral stenosis with special reference to coronary blood flow and myocardial oygen consumption. Circulation 22: 559, 1960... 16. Hellems, H. K., Ord, J. W., Talmers, F. N., and Christensen, R. C.: Effect of hypoxia on coronary blood flow and myocardial metabolism in normal human subjects. Coreulation 16:893, 1957. 17. Leight, L., DeFazio, V., Talmers, F. T., Regan, T. J., and Hellems, H. K.: Coronary blood flow, myocardial oxygen consumption and myocardial metabolism in normal and hyperthyroid human subjects. Circulation 14:90, 1956. 18. Rowe, G. G., Huston, J. H., Weinstein, A. B., Tuchman, H., Brown, J. F., and Crumpton, C. W.: The hemodynamics of thyrotoxicosis in man with special reference to coronary blood flow and myocardial oxygen consumption. J. Clin. Invest. 35:272, 1956. 19. Case, R. B., Griggs, D. M., Jr., and Pierson, R. N., Jr.: Determinations of the limit of reactivity of the coronary vascular bed. Circulation 22:731, 1960. 20. Shea, T. M., Watson, R. M., Piotrowski, S. F., Dermksian, G., and Case, R. B.: Anaerobic myocardial metabolism. Am. J. Physiol. 203:463, 1962. 21. Clark, A. J., Gaddie, R., and Stewart, C. P.: The anaerobic activity of the isolated frog's heart. J. Physiol. 75: 321, 1932. 22. Tennant, R.: Factors concerned in the arrest of contraction in an ischemie myocardial area. Am. J. Physiol. 113: 677, 1935. 23. Miiller, O., and R~rvik, K.: Haemodynamic consequences of coronary heart disease. Brit. Heart J. 20:302, 1958. 24. Johnson, J. B., Fairley, A., Carter, C.: Effects of sublingual nitroglycerine
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55 32. Freedberg, A. S., Spiegl, E. D., and Riseman, J. E. F.: Effect of external heat and cold on patients with angina pectoris: Evidence for the existence of a reflex factor. Am. Heart J. 27:611, 1944. 33. Riseman, J. E. F., and Stern, B.: A standardized exercise tolerance test for patients with angina pectoris on exertion. Am. J. M. Sc. 188:646, 1934. 34. Murray, M. J.: Effect of inspiration of cold air on electrocardiograms of normal humans with angina pectoris. Circulation 26:765, 1962. 35. Raab, W., Van Lith, P., Lepeschkin, E., and Herrlieh, H. C.: Catecholamineinduced myocardial hypoxia in the presence of impaired coronary dilatability independent of external cardiac work. Am. J. Cardiol. 9:455, 1962. 36. Arnett, E. L., and Watts, D. T.: Cateeholamine excretion in men exposed to cold. J. Applied Physiol. 15:499, 1960. 37. Raab, W.: Key position of catecholamines in functional and degenerative cardiovascular pathology, Am. J. Cardiol 5:571, 1960. 38. Sayen, Ji J., Kateher, A. H., Sheldon, W. F., and Gilbert, C. M.: The effect of levarterenol on polarographic myocardial oxygen, the epicardial electrocardiogram and contraction in nonischemic dog hearts, and experimental acute regional ischemia. Circulation 8:109, 1960.
Robert B. Case, M.D., Director, Laboratory of- Experimental Cardiology, and Associate Attending Physician, St. Luke's Hospital, New York City; Instructor in Medicine, Columbia University Medical College, New York City. Robert B. Roven, M.D., Postdoctoral Research Fellow, Nation Heart Institute, New York City.