The Use of Indirect Indices of Myocardial Oxygen Consumption in Evaluating Angina Pectoris
1973; Elsevier BV; Volume: 63; Issue: 3 Linguagem: Inglês
10.1378/chest.63.3.302-a
ISSN1931-3543
AutoresRobert E. Goldstein, Stephen E. Epstein,
Tópico(s)Cardiac Imaging and Diagnostics
ResumoEstimation of the patient's ability to perform exercise is an essential feature in the symptomatic evaluation of angina pectoris due to coronary artery disease. When practiced individuals perform work according to a suitable protocol, the duration of exercise necessary to precipitate ischemic chest pain (subsequently termed "exercise capacity") is reliably reproducible.1Redwood DR Rosing DR Goldstein RE et al.Importance of the design of an exercise protocol in the evaluation of patients with angina pectoris.Circulation. 1971; 43: 618Crossref PubMed Scopus (153) Google Scholar Since exercise capacity reflects the functional limits which circumscribe the activities of the patient, an accurate assessment of this quantity is vitally important in evaluating treatment programs and other interventions potentially influencing anginal symptoms. It is far more logical to use this measurement as an index of symptomatic status than highly subjective and variable quantities, such as the frequency of occurrence of chest pain or the number of nitroglycerin tablets consumed. Nevertheless, the use of exercise capacity as an index of a symptomatic change has important limitations. Muscular effort performed by the body is only indirectly related to cardiac stress. In contrast, a direct assessment of cardiac stress is provided by measuring myocardial oxygen consumption ( MV˙O2). Myocardial ischemia occurs during exercise when MV˙O2 increases sufficiently to exceed myocardial oxygen supply in regions where perfusion is restricted by diseased coronary arteries. Thus, the MV˙O2 at the onset of angina (" MV˙O2 at angina") is a measure of the maximum tolerated metabolic stress: interventions that increase MV˙O2 at angina (if there is no change in pain threshold) may be assumed to increase oxygen delivery to critically ischemic regions while interventions lowering MV˙O2 at angina may be thought to have an opposite action.2Goldstein RE Epstein SE Medical management of patients with angina pectoris.Progr Cardiovasc Dis. 1972; 14: 360Abstract Full Text PDF PubMed Scopus (29) Google Scholar In addition to altering the maximum tolerated MV˙O2 (ie, MV˙O2 at angina), interventions can also affect exercise capacity through a second, completely independent mechanism. By modifying exercise-induced changes in heart rate, blood pressure and other circulatory parameters which influence MV˙O2, interventions can modulate the MV˙O2 associated with any given level of skeletal muscle activity. Thus, a particular therapy can allow a patient to reach a previously unattainable exercise level by reducing the circulatory stress and resulting MV˙O2 associated with that work load, even though the therapeutic intervention has no effect on myocardial oxygen delivery and MV˙O2 at angina. Changes in MV˙O2 for a given work load and changes in MV˙O2 at angina must both be evaluated to comprehend fully the actions of an intervention affecting angina. The change in exercise capacity produced by an intervention represents the net result of the interplay between these two independent effects. As indicated in the foregoing discussion, knowledge of MV˙O2 at angina adds a degree of understanding not available from mere assessment of exercise capacity. It permits an important distinction between interventions affecting regional myocardial perfusion and interventions affecting myocardial oxygen requirements. Unfortunately, direct assessment of MV˙O2 in man is difficult. It requires measurement of myocardial arteriovenous oxygen (A-V O2) difference and of coronary blood flow ( MV˙O2 = coronary blood flow × A-V O2 difference). Each of these measurements is subject to significant error, particularly when coronary artery disease causes inhomogeneity of myocardial perfusion.3Klocke FJ Koberstein RC Pittman DE et al.Effects of heterogeneous myocardial perfusion on coronary venous H2 desaturation curves and calculations of coronary flow.J Clin Invest. 1968; 47: 2711Crossref PubMed Scopus (35) Google Scholar, 4Klocke FJ Wittenberg SM Heterogeneity of coronary blood flow in human coronary artery disease and experimental myocardial infarction.Amer J Cardiol. 1969; 24: 782Abstract Full Text PDF PubMed Scopus (28) Google Scholar In an effort to circumvent some of these problems, investigators have employed indirect indices of MV˙O2 that are readily quantified in exercising patients. One such index, the pressure-rate product, is based on the finding that MV˙O2 is directly related to both systolic blood pressure and heart rate.5Laurent D Bolene-Williams C Williams FL et al.Effects of heart rate on coronary flow and cardiac oxygen consumption.Am J Physiol. 1956; 185: 355PubMed Google Scholar, 6Sarnoff SJ Braunwald E Welch GHJR et al.Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension time index.Am J Physiol. 1958; 192: 148Crossref PubMed Scopus (693) Google Scholar, 7Katz LN Feinberg H Relation of cardiac effort to myocardial oxygen consumption and coronary flow.Circ Res. 1958; 6: 656Crossref PubMed Scopus (171) Google Scholar, 8Feinberg H Katz LN Boyd E Determinants of coronary flow and myocardial oxygen consumption.Am J Physiol. 1962; 202: 45PubMed Google Scholar Two additional indices, the so-called "tension-time index" (the integrated systolic pressure curve multiplied by heart rate) and the "triple product" of systolic pressure, heart rate and ejection time, incorporate the duration of systole as well as systolic blood pressure and heart rate in their indirect estimate of MV˙O2. Although early studies were consistent with the hypothesis that duration of systole significantly affected MV˙O2,8Feinberg H Katz LN Boyd E Determinants of coronary flow and myocardial oxygen consumption.Am J Physiol. 1962; 202: 45PubMed Google Scholar the importance of ejection time as a determinant of MV˙O2 subsequently has been questioned.9Monroe RG Myocardial oxygen consumption during ventricular contraction and relaxation.Circ Res. 1964; 14: 294Crossref PubMed Scopus (48) Google Scholar, 10Kitamura K Jorgensen CR Gobel F et al.Hemodynamic correlates of myocardial oxygen consumption during upright exercise.J Appl Physiol. 1972; 32: 516Crossref PubMed Scopus (444) Google Scholar Furthermore, recent studies in maximally exercising normal subjects suggest that the tension-time index may be less closely correlated with MV˙O2 than the pressure-rate product.10Kitamura K Jorgensen CR Gobel F et al.Hemodynamic correlates of myocardial oxygen consumption during upright exercise.J Appl Physiol. 1972; 32: 516Crossref PubMed Scopus (444) Google Scholar It should be noted that none of the indirect indices of MV˙O2 currently in use incorporates all of the factors known to exert a significant influence on MV˙O2. Modification of the contractile state of the myocardium (for example, the result of change in catecholamine stimulation) may greatly alter MV˙O2 independent of blood pressure and heart rate.11Sonnenblick EH Covell Jr, J Ross JW et al.Velocity of contraction as a determinant of myocardial oxygen consumption.Am J Physiol. 1965; 209: 919Crossref PubMed Scopus (152) Google Scholar Changes in MV˙O2 due to altered contractile state may well account for the lack of correlation of pressure-rate product or tension-time index with MV˙O2 during catecholamine infusion12Krasnow N Rollett EL Yurchak PM et al.Isoproterenol and cardiovascular performance.Am J Med. 1964; 37: 514Abstract Full Text PDF PubMed Scopus (110) Google Scholar or during excitement.13Rayford CR Khouri EM Gregg DF Effect of excitement on coronary and systemic energetics in unanesthetised dogs.Am J Physiol. 1965; 209: 680PubMed Google Scholar Similarly, geometric factors modifying ventricular wall stress, such as ventricular diameter, thickness and shape also exert an important influence on MV˙O2 that is not included in the indirect indices.14Monroe RG French GN Left ventricular pressure volume relationships and myocardial oxygen consumption in the isolated heart.Circ Res. 1961; 9: 362Crossref PubMed Google Scholar, 15Rodbard S Williams F Wiliams C The spherical dynamics of the heart (myocardial tension, oxygen consumption, coronary blood flow, and efficiency).Am Heart J. 1959; 57: 348Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 16Rollett EL Yurchak PM Hood Jr, WB et al.Pressure-volume correlates of left ventricular oxygen consumption in the hypervolumic dog.Circ Res. 1965; 17: 499Crossref PubMed Scopus (16) Google Scholar, 17Jorgensen CR Kitamura K Gobel FL et al.Long term precision of the N2O method for coronary flow during heavy upright exercise.J Appl Physiol. 1971; 30: 338Crossref PubMed Scopus (10) Google Scholar, 18Holmberg S Serzysko W Varnauskas E Coronary circulation during heavy exercise in control subjects and patients with coronary artery disease.Acta Med Scand. 1971; 190: 465Crossref PubMed Scopus (140) Google Scholar Thus, inference based on these indices must be circumscribed by the lack of precise information concerning the influence of changes in contractility and ventricular dimensions on MV˙O2. Considering the failure of the pressure-rate product to incorporate the influence of factors such as contractility and ventricular size, which are known to influence MV˙O2, it is remarkable how accurately the pressure-rate product correlates with values of MV˙O2 measured during upright exercise in man. Kitamura and coworkers10Kitamura K Jorgensen CR Gobel F et al.Hemodynamic correlates of myocardial oxygen consumption during upright exercise.J Appl Physiol. 1972; 32: 516Crossref PubMed Scopus (444) Google Scholar found that pressure-rate product increased linearly with MV˙O2 from rest through successive exercise levels to a maximum intensity of exercise sufficient to cause a four-fold rise in MV˙O2. The rapidity of coronary blood flow in heavily exercising subjects would appear to pose formidable problems for the nitrous oxide measurement technique they used to determine MV˙O2.17Jorgensen CR Kitamura K Gobel FL et al.Long term precision of the N2O method for coronary flow during heavy upright exercise.J Appl Physiol. 1971; 30: 338Crossref PubMed Scopus (10) Google Scholar Nevertheless, their results appear to demonstrate an impressive ability of the pressure-rate product to predict MV˙O2 (r = 0.90). These studies, however, were performed in well-conditioned, young normal subjects, and the results may not necessarily be applicable to an older population or to patients with coronary artery disease. A similar correlation of the pressure-rate product and MV˙O2 has been attempted in patients with coronary artery disease,18Holmberg S Serzysko W Varnauskas E Coronary circulation during heavy exercise in control subjects and patients with coronary artery disease.Acta Med Scand. 1971; 190: 465Crossref PubMed Scopus (140) Google Scholar but difficulties related to inhomogeneous myocardial blood flow make interpretation of the significance of these data difficult. A definitive assessment of the value of pressure-rate product (and the relative merit of different indirect indices of MV˙O2) in this context will require an increased sophistication in techniques for measuring MV˙O2. In addition to uncertainties in the relation between indirect indices of MV˙O2 and MV˙O2 itself, further problems in interpretation arise when a therapeutic intervention changes both MV˙O2 and circulatory variables such as blood pressure, heart rate, or left ventricular filling pressure. In addition to altering MV˙O2, each of these circulatory variables is associated with complex mechanical effects that may themselves change the delivery of blood flow to ischemic regions. Thus, increased diastolic blood pressure augments perfusion through collateral channels19Brown BG Gundel WD Gott VL et al.Hemodynamic determinants of retrograde arterial coronary flow following acute coronary occlusion.Circulation. 1972; 46: 100Google Scholar tending to counterbalance the deleterious affects of the increase in MV˙O2 due to a rise in systolic pressure. On the other hand, increases in heart rate not only raise MV˙O2, but also diminish the duration of diastole, the time when significant coronary collateral flow occurs.19Brown BG Gundel WD Gott VL et al.Hemodynamic determinants of retrograde arterial coronary flow following acute coronary occlusion.Circulation. 1972; 46: 100Google Scholar Finally, an increase in left ventricular filling pressure not only raises myocardial wall tension, thereby augmenting MV˙O2, but it may also cause an unfavorable redistribution of coronary flow through its mechanical effects on major endocardial coronary collaterals.20Becker LC Fortuin NJ Pitt B Effect of ischemia and antianginal drugs on the distribution of radioactive microspheres in the canine left ventricle.Circ Res. 1971; 28: 283Crossref Scopus (275) Google Scholar From these considerations it is apparent that a given increase in pressure-rate product or triple product might have different implications regarding the critical balance between myocardial oxygen supply and demand depending upon whether that increase was due to a rise in heart rate or to a rise in blood pressure. In the former case, the rise in heart rate would not only augment myocardial oxygen demands, but also tend to diminish the time available for coronary collateral flow. In the latter case, however, the rise in blood pressure, in addition to its effects on increasing MV˙O2, would actually tend to enhance collateral flow. The constancy of the pressure-rate product21Robinson BF Relation of heart rate and systolic blood pressure to the onset of pain in angina pectoris.Circulation. 1967; 35: 1073Crossref PubMed Scopus (392) Google Scholar or the triple product1Redwood DR Rosing DR Goldstein RE et al.Importance of the design of an exercise protocol in the evaluation of patients with angina pectoris.Circulation. 1971; 43: 618Crossref PubMed Scopus (153) Google Scholar, 21Robinson BF Relation of heart rate and systolic blood pressure to the onset of pain in angina pectoris.Circulation. 1967; 35: 1073Crossref PubMed Scopus (392) Google Scholar in a given patient at onset of angina suggests that changes in myocardial oxygen delivery to ischemic regions resulting from alterations in blood pressure, heart rate or duration of systole may not be of great practical importance. Nevertheless, none of these circulatory parameters used to estimate MV˙O2 indirectly exists in isolation—all have the potential ability to effect blood flow to ischemic regions as well as MV˙O2. Despite their limitations and uncertainties, indirect indices of MV˙O2 have been of some value in at least tentatively distinguishing between those interventions altering exercise capacity in angina patients by modifying the circulatory response to exercise and those interventions that appear to alter exercise capacity by changing myocardial oxygen delivery to ischemic regions. Thus, the deleterious effects of a meal,22Goldstein RE Redwood DR Rosing DR et al.Circulatory response to exercise following a meal and their relationship to postprandial angina pectoris.Circulation. 1971; 44: 90Crossref PubMed Scopus (55) Google Scholar cigarette smoking,23Aronow WS Kaplan MA Jacob D Tobacco: a precipitating factor in angina pectoris.Ann Intern Med. 1968; 69: 529Crossref PubMed Scopus (44) Google Scholar or a cold environment24Epstein SE Stampfer M Beiser GD et al.Effects of a reduction in environmental temperature on the circulatory response to exercise in man.N Engl J Med. 1969; 280: 7Crossref PubMed Scopus (82) Google Scholar and the beneficial effects of electrical carotid sinus nerve stimulation25Epstein SE Beiser GD Goldstein RE et al.Treatment of angina pectoris by electrical stimulation of the carotid-sinus nerves.N Engl J Med. 1969; 280: 971Crossref PubMed Scopus (43) Google Scholar are evidently mediated by altered circulatory stresses since pressure-rate product at angina is unchanged. Saphenous vein bypass is followed by an augmented pressure-rate or triple product26Amsterdam EA Iben A Hurley EJ et al.Saphenous vein bypass graft for refractory angina pectoris: physiologic evidence for enhanced blood flow to ischemic myocardium.Am J Cardiol. 1970; 26: 623Abstract Full Text PDF Google Scholar at angina, possibly due to an increase in perfusion of ischemic regions (if one is willing to set aside the possibility of infarction of ischemic tissue or alteration of its nervous connections). Physical training clearly exerts some of its beneficial effects on exercise capacity by attenuating circulatory stresses, thereby lowering myocardial oxygen requirements for any given level of activity.27Redwood DR Rosing DR Epstein SE Circulatory and symptomatic effects of physical training in patients with coronary artery disease and angina pectoris.N Engl J Med. 1972; 286: 959Crossref PubMed Scopus (136) Google Scholar Whether physical training actually improves myocardial oxygen delivery, however, remains ambiguous: the pressure-rate product at angina remains constant, but prolongation of ejection time yields an increased triple product at angina in some patients.27Redwood DR Rosing DR Epstein SE Circulatory and symptomatic effects of physical training in patients with coronary artery disease and angina pectoris.N Engl J Med. 1972; 286: 959Crossref PubMed Scopus (136) Google Scholar Drug studies are similarly ambiguous due to the complexity of most drug actions. Nitroglycerin28Detry J-MR Bruce RA Effects of nitroglycerin on "maximal" oxygen intake and exercise electrocardiogram in coronary heart disease.Circulation. 1971; 43: 155Crossref PubMed Scopus (51) Google Scholar, 29Goldstein RE Rosing DR Redwood DR et al.Clinical and circulatory effects of isosorbide dinitrate: comparison with nitroglycerin.Circulation. 1971; 43: 629Crossref PubMed Scopus (123) Google Scholar and isosorbide dinitrate29Goldstein RE Rosing DR Redwood DR et al.Clinical and circulatory effects of isosorbide dinitrate: comparison with nitroglycerin.Circulation. 1971; 43: 629Crossref PubMed Scopus (123) Google Scholar increase pressure-rate product at angina; while this result may be caused by an improvement in delivery of blood to ischemic regions, it also may be due to reduced ventricular dimensions or possibly reduced duration of systole lowering MV˙O2. During subanginal levels of exercise, the nitrates reduce the pressure-rate product at a given level of activity. However, this reduced pressure-rate product encompasses a much decreased blood pressure and a moderately increased heart rate. Since both of these changes tend to diminish coronary collateral flow (as indicated previously), it is unclear whether the reduction in MV˙O2 implied by lower pressure-rate product outweighs the potentially deleterious actions on collateral flow. Thus, it is not certain whether the beneficial effects of the nitrates can be ascribed to the reduction in arterial pressure, or whether a direct effect on coronary blood flow must be involved. Treatment with beta receptor blocking agents also lowers pressure-rate product2Goldstein RE Epstein SE Medical management of patients with angina pectoris.Progr Cardiovasc Dis. 1972; 14: 360Abstract Full Text PDF PubMed Scopus (29) Google Scholar and MV˙O230Jorgensen CR Wang K Gobel FL et al.Effect of propranolol on myocardial oxygen consumption and its hemodynamic correlates during upright exercise.Circulation. 1972; 46: 171Google Scholar for a given work load. In this instance, the change in pressure-rate product is achieved largely by a reduction in heart rate, thus favoring collateral flow, with relatively little change in arterial pressure. However, it should be noted that pressure-rate product is reduced at angina following propranolol31Robin E Cowans C Puri P et al.A comparative study of nitroglycerin and propranolol.Circulation. 1967; 36: 175Crossref PubMed Scopus (71) Google Scholar, 32Sowton E Hamer J Hemodynamic changes after beta adrenergic blockade.Am J Cardiol. 1966; 18: 317Abstract Full Text PDF PubMed Scopus (61) Google Scholar or practolol,33Wolfson S Phillips SL Schecter E Effects of specific myocardial beta blockade in angina pectoris.Am J Cardiol. 1970; 26: 666Abstract Full Text PDF Google Scholar possibly the result of increased ventricular size, which tends to augment MV˙O2. The reduction in pressure-rate product at angina mitigates against a decisively important influence of propranolol on improving coronary flow distribution20Becker LC Fortuin NJ Pitt B Effect of ischemia and antianginal drugs on the distribution of radioactive microspheres in the canine left ventricle.Circ Res. 1971; 28: 283Crossref Scopus (275) Google Scholar or oxygen release34Manchester JH Shelburne JC Oski FA et al.Relationship of antianginal agents to hemoglobin-oxygen affinity.Circulation. 1972; 46: 28Google Scholar since such an action would be expected to result in an increase in pressure-rate product at angina. In summary, measurement of indirect indices of MV˙O2 expands the scope of information obtained when exercise tests are performed by angina patients. Inferences drawn from these data, however, must be carefully circumscribed because 1) the predictive value of these indices has not been fully validated in angina patients, 2) the indices do not incorporate potentially important changes related to myocardial contractility and ventricular dimensions and 3) changes in one or more of the circulatory parameters (eg heart rate or blood pressure) included in the indirect indices may alter delivery of myocardial blood flow as well as MV˙O2. Systolic Blood Pressure, Heart Rate and Treadmill Work at Anginal ThresholdCHESTVol. 63Issue 3PreviewSystolic blood pressure, heart rate, rate-pressure product and treadmill work time at the last moment of exercise in 189 graded exercise tests were examined for relationships with age and the pressure or absence of angina pectoris. Exercise heart rate and treadmill work time were equally related to diagnosis (r2=.33) and in normal patients both declined with age. Exercise systolic blood pressure increased with age and was not related to diagnosis. Rate-pressure product was unrelated to age of subject but was weakly related to diagnosis. Full-Text PDF
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