Characterization

of the lschemic

Process by Regional

Metabolism NORMAN New

BRACHFELD.

York, New

MD,

FACC

York

The myocardial cell requires energy for contractile activity and for the work of internal maintenance. With the onset of ischemia mechanical performance is compromised. If the ischemia is severe and persistent, the energy necessary to maintain the internal milieu proves inadequate and cell death ensues. lschemic heart disease is a regional phenomenon with normal and abnormal cell metabolism occurring side by side. The ischemic cell demonstrates hemodynamic, electrical and biochemical instability; its passage from a state of reversible to irreversible injury may persist for as long as 7 days and offers an opportunity to introduce interventions that may protect it and reduce ultimate infarct size. There is as yet no adequate objective means for predicting the mass of infarcted tissue. However, studies of regional metabolism, if properly conducted, may help define the adequacy of coronary vascular reserve and characterize the ischemic process. Current techniques utilize a myocardial pacing stress to induce an ischemic response. Although virtually every metabolic pathway is disrupted by severe ischemia, the assay of selected metabolites in arterial and coronary venous blood samples has provided information of diagnostic significance.

The myocardial cell functions as an isothermal biochemical engine that converts the potential chemical energy of metabolic fuel into a storage form, the high energy phosphate compounds. These in turn are utilized to energize the contractile mechanisms necessary to meet the demands for external contractile work, to maintain active transport of molecules, to synthesize macromolecules and other biomolecules from precursors and to generate high energy compounds by oxidation of substrate. The latter noncontractile activities are expressions of the biochemical “work” of maintaining an optimal cellular milieu necessary to sustain viability. Biological

From the Department of Medicine, Division of Cardiology, The New York Hospital-Cornell Medical Center, New York, N. Y. 10021. Address for reprints: Norman Brachfeld, MD, The New York Hospital-Cornell Medical Center, 525 East 68th St., New York, N. Y. 10021.

Function

of the Heart

in lschemia

Any disruption of the multiple chemical reactions necessary to maintain this energy-producing and energy-utilizing cycle must be reflected by mechanical and electrical malfunction as well as by measurable distortions of virtually every metabolic pathway. The clinical, hemodynamic and electrical expression of interference in the pattern of aerobic metabolism is the result, not the cause, of these metabolic changes. An important parameter of myocardial disease, regardless of origin, may be defined in terms of a biochemical defect that interferes with the chemical transformation of sufficient amounts of substrate energy into useful electrical, mechanical and biochemical work. The primary biologic function of the heart is that of a fluid pump, and well over 90 percent of the energy normally produced by consumption of substrate and oxygen is utilized to support contractile

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activity. We have traditionally evaluated the function or malfunction of the heart in mechanistic terms of contractile activity. Nevertheless, it retains all of the synthetic and biologic potential of every other cell of the body. The “work” required to maintain an appropriate internal cellular environment for metabolic and hemodynamic function is relatively fixed. A significant reduction in oxygen consumption is first expressed by a decrement in mechanical activity so that the work of internal maintenance consumes a proportionately greater percentage of total oxygen consumption. This utilization of marginal supplies of oxygen has widespread biologic ramifications. Ischemic heart disease is a regional rather than a global phenomenon. It leads to the creation of multiple border zones consisting of cell populations with differing metabolic and hemodynamic expressions. Heart failure is a relatively infrequent occurrence. Thus we deal not with a disease of the heart as a whole but with small scattered myocardial segments, usually less then 20 percent of the total mass. As a result of this distribution we find essentially normal cells, consuming energy at normal or supernormal rates and utilizing it to perform mainly contractile work, lying adjacent to cells that may be contracting poorly or not at all and whose energy utilization may be devoted almost entirely to the maintenance of viability. Measurement

of Infarct Size

It is barely 15 years since the first hospital units specifically dedicated to the care of patients with myocardial infarction were inaugurated in this country. Continuous electrocardiographic monitoring and use of antidysrhythmic drugs and electrical cardioversion and defibrillation have substantially reduced mortality from previously lethal dysrhythmias. Unfortunately, mortality rates related entirely to the quantitative amount of ischemic or necrotic myocardium remain alarmingly high. The recent interest in the development of techniques designed to protect the ischemic myocardium and reduce infarct size is an attempt to move away from this therapeutic plateau and indicates a potentially new era in the approach to ischemic heart disease. There has been a progression from monitoring and treating dysrhythmias as they occurred to the aggressive use of antidysrhythmic drugs and more recently to the application of interventions developed to support ischemic, but viable, tissue. These include vagal stimulation, counterpulsation, early and delayed reperfusion and the administration of drugs including nitrogylcerin, nitroprusside, propranolol and other beta adrenergic blocking agents, mannitol, the antilipolytic verapamil, methylprednisolone, agent beta-pyridyl-carbinol, trimethaphan, hyaluronidase, glucose or glucose-insulin-potassium mixtures and cobra venom factor. Evaluation of such interventions requires an adequate animal model for experimental study and an

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accurate, objective, easily used method for measuring the mass of ischemic or infarcted myocardium or for predicting ultimate infarct size. Unfortunately, neither of these requirements has been met as yet. Epicardial S-T segment mapping: Results of this method have generally shown a good correlation with results of subsequent pathologic study. Unfortunately, extrapolation to precordial mapping has proved less than satisfactory in many hands. Its use as a quantitative tool is challenged by our ignorance of the true causes of such distortions of membrane polarization. S-T segment changes certainly demonstrate deterioration of repolarization but are nonspecific reflections of disturbances in ion transport or energy metabolism and may be seen in such nonischemit processes as those associated with the cardiomyopathies and pericardial disease. Serum CPK: Quantitation of infarct size by serial determination of creatine phosphokinase (CPK) activity requires a delay before administration of a planned intervention, is less accurate than was initially suggested and requires multiple biochemical determinations and availability of computer time for curve-fitting techniques that permit comparison of projected CPK values to serial changes actually observed. Increasing awareness of clearance rates, serum and tissue factors and other mechanisms responsible for serum concentrations has indicated that these calculations are more difficult than anticipated. There is a rapid temperature-related and sometimes unpredictable breakdown of CPK within tissue and a high activation energy. An increase in body temperature of lo, often seen with acute myocardial infarction, may increase the error of the determination by as much as 20 percent. The use of CPK isoenzyme determination may improve the accuracy of this procedure. Radioisotope myocardial imaging: Efforts to improve the definition of myocardial imaging by accumulation of radioisotope in the area of ischemia or surrounding normal myocardium hold promise for the future and appear to be especially well suited for evaluation of those interventions that might improve nutritional flow. Clinical implication: There is currently no consistently effective simple means for measuring myocardial infarct size in man. The clinical application of many of the interventions described has been extrapolated from animal studies. However promising they may appear to be, cardiologists have been unable to utilize them adequately in vivo and provide objective evidence of ability to protect the ischemic myocardium or reduce infarct size. Encouraging results must be interpreted by less than satisfactory prospective epidemiologic data evaluation. Myocardial

Metabolism

In 1947 Bing et a1.l reported catheterization of the coronary sinus and middle cardiac vein in man and soon exploited this technique to describe the normal

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myocardial patterns of substrate utilization. The development of techniques that permitted measurement of coronary flow in vivo and application of sophisticated biochemical assay methods led to the evaluation of pathways utilized in the cellular metabolism of the major substrate classes under normal and abnormal conditions. The heart was shown to demonstrate wide substrate adaptability and to be capable of utilizing most nutritional substances. It normally extracted glucose, pyruvate, lactate and free fatty acids but was capable of consuming acetate, ketone bodies and amino acids under appropriExtraction patterns were inate circumstances. fluenced by many factors including absolute and relative arterial concentrations and the permeability of the plasma membrane that set transport thresholds. Oxidative metabolism was shown to be markedly flow-dependent since oxygen extraction was near maximal at rest. An increase in demand for available free energy, most often induced by an increase in work, showed an almost linear correlation with enhancement of coronary flow. Clinical application: Wollenberger2 and Olson” suggested that a defect in myocardial energetics may be induced by an insufficient production of energy (liberation), a defective storage of energy (conservation) or an inability to utilize energy efficiently (utilization). They established a structure in which biochemical data that had previously been of essentially academic interest could be utilized in a clinical setting. Although these early studies introduced many important concepts, it soon became apparent that they were less applicable to patients than to experimental animal studies and to evaluation of normal myocardial metabolism in the truly resting state. They were subject to all of the limitations imposed by intact biologic systems and often failed to detect subtle changes in metabolic balance. They assumed homogeneous myocardial perfusion and steady state performance. Substrate storage and dilutional problems introduced by metabolic pools often occurred so that consumption of substrate could not be equated with utilization unless isotopic substrate labeling was performed. Explanations for the infrequent but puzzling lack of reproducibility when metabolic pacing stress studies were performed in patients with coronary artery disease have only recently been offered. Recent modifications of pacing-sampling techniques have enhanced their diagnostic value. lschemic

Tissue Injury

A major impediment to these early studies was our naive assumption that myocardial infarction was an all or none type of injury with a central zone of homogeneously necrotic tissue surrounded by a slim periphery of ischemic myocardium. Pathologic reports revealed this to be a false premise, and we have come to realize that the margin between myocardial cell life and death may be difficult to define accurately. Metabolism implies living tissue. The processes of ischemic metabolism are dynamic phenomena in a

CHARACTERIZATION

OF

ISCHEMIA-BRACHFELD

constant state of flux, changing in degree and severity and influenced by many hemodynamic, biochemical and pharmacologic factors. The ischemic cell displays both electrical and biochemical instability, and its viability depends upon its ability to produce sufficient high energy phosphate to maintain cellular homeostasis. Cellular ischemia may be said to exist when reduction in arterial flow proves insufficient to meet oxygen demand.4 Since this imbalance between oxygen supply and demand is neither fixed nor persistent but subject to variations induced by changes in hemodynamic performance, the myocardial infarct presents as a heterogeneous mixture of constantly changing proportions of cells demonstrating normal, mild, moderate and severe ischemic metabolism. Adequate perfusion may be prevented not only by a decrease in perfusion pressure and flow induced by large vessel insufficiency, but also by a temporary increase in peripheral myocardial vascular resistance secondary to arteriolar vasconstriction, an increase in intramyocardial pressure, a reduction in capillary perfusion due to endothelial cell swelling or to a raterelated decrease in diastolic perfusion time. Quantification of severity of ischemia: A remarkable series of studies reported by Jennings et a1.5 has established an optical and electron microscopic basis for this concept. Their use of nuclidelabeled microspheres to yield sequential instantaneous estimates of local blood flow have confirmed that it is possible to quantitate regional differences in depressed flow and thus of severity of ischemia within the same zone. Both vasoreactivity and the anatomic location of collateral flow channels supplied by arteriolar and larger anastomoses determines the supply of potential nutritional flow. This nonuniformity of ischemic injury, with necrotic cells mixed with normal, mildly, moderately and severely ischemit cells, is further complicated by existence of a transmural flow gradient with oxygen tension (POz) reduced more in the subendocardium than in the subepicardium as well as by lateral gradients, which indicate that the center of the ischemic zone receives less flow than does the periphery.5 These anatomic gradients are accompanied by metabolic transmural tissue gradients for glycogen, lactate and high-energy phosphate.6,7 Reversible versus irreversible ischemic damage: There is rarely a sharp line of demarcation between reversible and irreversible ischemic damage. Necrosis may be evident as early as 20 minutes after cessation of primary vessel flow and be progressive, with more and more cells succumbing over a period of 24 hours.8,g Jennings et a1.8 have also reported experiments that established histologic evidence of irreversibility, that is, necrosis or scarring occurring 1 to 7 days after reflow. These studies and those of-Alonzo et al.1° indicate that myocardial infarction is not a completed process upon admission to hospital and demonstration of diagnostic electrocardiographic and serum enzyme changes. They indicate a continuum of changes with probable progression of necrosis and ex-

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tension of the initial area of infarction for hours or days after the patient comes under observation. The possibility of therapeutic intervention is thus a very real challenge for the future. Regional

Myocardial

Metabolism

The introduction of surgical and medical techniques designed to restore flow to the ischemic cells or protect the ischemic myocardium by restoring the balance between flow and demand makes it of more than academic interest to be able to determine, with some degree of precision, the severity of myocardial ischemia and the anatomic location of this tissue. The biochemical characterization of ischemic myocardium has as its major focus the identification of ischemic, yet viable and potentially salvageable myocardium that, without successful intervention, is almost certainly destined to be transformed into infarcted tissue. Once this has occurred, restoration of coronary blood flow can do little to improve myocardial function. Continuous refinement of techniques, improvement in assay sensitivity and selection of the metabolic variables to be measured may provide a framework that will make it possible to quantify and predict the extent of injury, determine its degree of reversibility and help select and provide a benchmark for evaluating optimal intervention. Assay of blood samples draining the zone of ischemia: Coronary artery disease is most often seg-

mental and may involve one or more vessels with various degrees of severity. Multiple collateral pathways invariably produce a nonuniform distribution of perfusion. The absence of biochemical evidence of ischemia after cardiac pacing in patients with known coronary disease often occurs as a result of mixing problems when drainage from ischemic zones is diluted by effluent flow from normal areas of the left ventricle. Mixing of effluent from tissues with different metabolic rates may induce a variety of errors in interpretation. Furthermore, if the coronary effluent from the ischemic zone drains into the coronary sinus proximal to the position of the tip of the catheter it will not be sampled. The introduction of multiple site sampling of myocardial venous drainage by Herman et al.” has improved our ability to detect and localize regional abnormalities. This clinical study was confirmed by evaluation of regional metabolic changes in the myocardium after ligation of the anterior descending artery of the dog.12 Samples of venous effluent drawn from a position deep in the great cardiac vein were compared with those taken from the ostia of the coronary sinus.12 Confirmation was also obtained by Owen et a1.13 in experiments that compared metabolic changes in local venous and coronary sinus blood after acute coronary arterial occlusion. Corday et al. l4 have emphasized that the metabolic consequences of coronary occlusion are best studied by assay of samples draining the zone of ischemia. When the left circumflex artery is experimentally occluded, drainage from the great cardiac vein

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represents the venous return from the nonischemic zone perfused by the left anterior descending coronary artery. They have described an experimental intracoronary balloon catheter that separates the venous blood draining occluded and nonoccluded segments and allows assessment of regional myocardial oxygen and substrate metabolism in the closed chest dog. Diagnostic

Implications of lschemic Changes

Metabolic

Hoffstein et al.t5 have utilized colloidal lanthanum to demonstrate that an early event in the pathogenesis of ischemic cell damage is injury to the plasma membrane and increased permeability to ions and macromolecules before overt structural changes appear. Although virtually all metabolic pathways are affected by a critical reduction in flow, our ability to demonstrate abnormal arteriovenous differences for specific compounds at rest, after a myocardial infarction or after a pacing-induced stress, is determined by many factors including membrane binding and permeability, the severity of ischemia, the sensitivity of our assays, sampling sites and times, the nutritional state of the patient and other factors. Although apparently paradoxical, it is evident that with total cessation of flow tissue metabolism becomes completely anaerobic and soon ceases. Although abnormal metabolic intermediates will accumulate within the cell, the absence of washout will preclude appearance of such substances in venous drainage. As one progresses to areas of moderate to mild ischemia, flow ensures that substrate will reach the injured cells and energy production can proceed by means of a mixture of aerobic and anaerobic metabolism. Washout can occur and venous sampling will provide evidence of abnormal metabolism. Mildly ischemic tissue probably provides the greatest amount of these by-products.5J6 Pacing-induced ischemia: Venous sampling after pacing-induced ischemia has proved of particular value in evaluating patients with atypical chest pain, normal resting and exercise electrocardiograms and angiograms. compatible with moderate coronary artery disease. Such patients often pose difficult diagnostic and therapeutic problems that may be resolved by evidence of ischemic metabolism. This approach is equally applicable for determining the effectiveness of surgical or pharmacologic intervention for coronary artery disease. If proper precautions are taken in the interpretation of data, it is often possible to resolve rapidly a puzzling clinical dilemma.17 Pacing-induced ischemia in man is associated with augmented glucose extraction that is unrelated to arterial glucose concentration.18 Changes in free fatty acid metabolism may also be extremely sensitive to alterations in oxygen availability. Patients with normal nutritional flow show an enhancement of myocardial fractional extraction of free fatty acids during pacing. In those with pacing-induced ischemia there

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is a reversal of the normal pattern.lg Extraction decreases but oxidation of the free fatty acids transported into the cell is significantly increased. Pacing-Induced Myocardial Lactate Metabolism Pacing-Induced &hernia

lschemia After

Clues to enhanced anaerobic metabolism expressed as a decrease in lactate extraction or evidence of lactate production are commonly utilized to demonstrate enhanced anaerobic glycolytic activity. The inability of the tricarboxylic acid (Krebs) cycle pathway to utilize the increased amounts of pyruvate generated by enhanced glycolysis and the accumulation of cytoplasmic NADH forces the conversion of pyruvate to lactate for disposal of protons and oxidation of the reduced form of nicotinamide-adenine dinucleotide (NADH). A reduction in the supply of oxygen to the myocardial cell causes a shift in its oxidation-reduction system to a more reduced state. The oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD, NADH) and the NADlinked dehydrogenase systems immediately reflect this change. Our primary concern, however, is with the NAD/NADH redox potential of the mitochondrion, the site of oxidative phosphorylation and the most sensitive index of the adequacy of oxidation. The intramitochondrial redox state is only indirectly coupled to cytoplasmic NAD-NADH ratios and the latter is grossly reflected by relative shifts in intracellular lactate/pyruvate concentrations. Estimation of myocardial ischemia from myocardial venous lactate data: Such changes in veconcentrations are many nous lactate/pyruvate stages removed from the critical site at the mitochondrial level. Venous concentrations represent mixed samples and at best express a net lactate balance. Myocardial ischemia has been qualitatively expressed in terms of a decrease in lactate extraction (percent lactate extraction), release of lactate into coronary venous blood samples (lactate production), or as an increase in the lactate/pyruvate ratio. The validity of this type of estimation requires that the muscle cell membrane be freely permeable to lactate and pyruvate and that there be an equilibrium between cytoplasmic and mitochondrial NADH concentration, assumptions that are not entirely justified. If the clinician is aware of potential pitfalls, misinterpretation may be avoided and this extrapolation considered valid for all practical purposes.20 Table I lists some of the factors of importance in evaluating myocardial venous lactate data. Although patients with myocardial ischemia may show evidence of enhanced glycolysis when coronary reserve is challenged, myocardial glycolysis is accelerated by many factors in the absence of coronary artery disease and despite adequate oxygenation. If the capacity of the hydrogen shuttle is exceeded, lactate may be formed from pyruvate.

TABLE

OF ISCHEMIA-BRACHFELD

I

Significant --___

Factors in Evaluating -__-__-

Myocardial -__

Lactate

Data __--

1. Nutritional status of the patient a. Infusion of glucose, pyruvate or lactate (there is a positive linear correlation between lactate extraction and arterial lactate concentration 1 b. Shock, hypoxia (arterial lactate level is elevated in these conditions) c. Diabetes d. Elevated serum free fatty acid concentration (this may suppress extraction of carbohydrate and induce pyruvate efflux) 2. Alkalosis, hyperventilation, infusion of bicarbonate 3. Catheter placement, inadequate sampling, segmental disease a. Sampling site proximal to vein draining ischemic area b. Meager or absent drainage from ischemic areas c. Dilution of ischemicdrainage by normal venous efflux

Sources of error in diagnostic pacing studies: Pacing studies should not be performed unless the subject is in a steady (basal) nutritional, metabolic and hormonal state. Sampling after an overnight fast during a period of active metabolism of elevated free fatty’acids is accompanied by suppression of circulating glucose, lactate and pyruvate concentration as well as inhibition of pyruvate dehydrogenase activity so that an increased amount of pyruvate is converted to lactate. Glycolysis is also depressed by citrate-induced inhibition of phosphofructokinase activity, extraction of carbohydrate is reduced and myocardial arteriovenous differences are difficult to determine accurately. Starved rats show a decrease in their myocardial lactate/pyruvate ratio. Conversely, hyperglycemia induced by glucose infusion will enhance its extraction and both pyruvate and lactate production, prevent steady state determinations, and induce a transit time artifact.21 Exercise stress tests, once popular for evaluation of coronary insufficiency, are compromised when utilized for estimation of myocardial glycolysis because of the accompanying increase in arterial lactate concentration and have been replaced by pacing-induced stress. Shock and generalized hypoxia from whatever cause are also associated with marked elevations in arterial lactate concentration and are a contraindication for coronary sinus studies. Henderson et a1.22 have postulated compartmentation of tissue lactate and demonstrated differing transmembrane concentration gradients for lactate and pyruvate. The rate of pyruvate efflux from the isolated heart was shown to exceed that of lactate by lo-fold. Some investigators have therefore abandoned pyruvate determinations and lactate/pyruvate ratios in favor of a lactate assay alone, recognizing that the loss in sensitivity is compensated for by an increased reliability. The relative inhibition of membrane transport of glucose found in diabetes mellitus reduces glycolytic flux and is associated with a decrease in lactate/pyruvate ratio and with pyruvate accumulation. In studies performed with the isolated diabetic heart, the addition of insulin enhanced glycolytic flow, but

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pyruvate accumulation persisted. Further, the elevation in circulating free fatty acids and ketone bodies noted in poorly controlled diabetes leads to citrate induced inhibition of phosphofructokinase activity and further depresses glycolysis. Both free fatty acids and ketone bodies are extracted from the arterial blood in preference to lactate and, when present in significant concentrations, will distort the lactate/ pyruvate ratios of the coronary venous samples and cause a misleading decrease in the calculated percent of lactate extraction. Enhanced insulin resistance or latent diabetes, frequently noted in the postcoronary state, must also be considered when such studies are performed. Other hormones and drugs (growth hormone, cortisol, heparin) modulate glycolytic flux by mobilization of free fatty acids. Perhaps the most common mechanism for the mobilization of free fatty acids from adipose depots is that stimulated by an increase in catecholamine secretions. Patients undergoing diagnostic pacing studies often demonstrate anxiety symptoms and elevated blood catecholamine levels, especially when the heart is paced to the onset of angina. Finally, it must be noted that glucagon has been shown to accelerate conversion of phosphorylase “b” to “a,” thus enhancing glycogenolysis and increasing the output of lactate. Scheuer and Berryz3 reported that alkalosis increased myocardial lactate production and increased exogenous glucose and endogenous glycogen utilization during normal oxygenation. These effects were noted whether pH changes occurred as a result of reducing carbon dioxide tension (PCOs) or by increasing the bicarbonate content. Its mechanism appears to be a stimulation of phosphofructokinase activity. The Pasteur effect is disrupted by alkalosis since phosphofructokinase activity is relieved from adenosine triphosphate inhibition by an elevation of pH. During hypoxia, metabolic alkalosis was associated with improved ventricular pressure and rate of pressure rise, neither oxygen consumption nor lactate production was increased, and lactatelpyruvate ratios were lower than in control studies. Huckabeez4 also reported lactate production in hyperventilating human subjects. Thus alkalosis alone may double lactate production. It, is evident that evaluation of lactate data may be inconclusive without simultaneous determination of pH, bicarbonate concentration, arteriovenous glucose, and free fatty acid levels. Hexokinase and phosphofructokinase activity may be accelerated in the isolated heart preparation by an acute increase in work. 25 Glucose and glycogen consumption increases, as does output of lactate and pyruvate. Lactate production is similarly doubled when contractility is enhanced by increasing the calcium concentration of perfusate solutions.26 Other more exotic causes of lactate production in the face of normal oxygenation include cardiac transplantation, uncoupling or interruption of the respiratory chain

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by cyanide, a variety of idiopathic cardiomyopathies, phenformin-induced and idiopathic lactic acidosis, and alcohol ingestion. Alcohol increases cytoplasmic hydrogen ion content at a rate greater than that at which it can be shuttled to the mitochondrion for oxidation Despite great care, one may still fail to obtain evidence of ischemia by reliance on evidence of anaerobic glycolysis alone. It would seem wise to evaluate simultaneously several variables during pacing-induced stress. Further Diagnostic Metabolic Abnormalities Associated With Pacing-induced lschemia

A negative potassium balance induced by pacing was reported by Parker et a1.27 and demonstrated experimentally by Opie et a1.28 in hearts whose ischemit zone constituted more than 15 percent of total heart volume. Opie et al. also reported an increase in coronary venous inorganic phosphate that exceeded arterial concentration by more than 15 to 20 percent and was believed to reflect the intracellular breakdown of high energy phosphate compounds. Fox et a1.2g reported the release of adenosine into coronary sinus blood of patients undergoing pacing to the onset of angina and found such release to be a valuable supplementary index of the early effects of ischemia on myocardial metabolism. Berger et al.so recently described release of prostaglandin F after pacing in 11 of 12 patients with coronary artery disease. Although the precise site of release of prostaglandin F was not known, the correlation of release with regional myocardial ischemia suggested that this potent substance may also play a physiologic role in the cardiac response to ischemia. Bradykinin, another physiologic vasoactive substance, has been identified in the coronary venous effluent of patients with significant coronary artery disease.:” Alterations in amino acid metabolism with release of alanine have also been observed both at rest and after pacing.s2 A reduction in venous pH and oxygen desaturation of venous samples often, although not invariably, accompanies pacing-induced angina. Clinical

Implications

The initial impact of the coronary care concept on mortality from myocardial infarction has been consolidated and recent experimental reports indicate that we are entering into a new phase in the treatment of coronary insufficiency and myocardial ischemia, one that stresses cellular support of the threatened myocardium rather than acceptance of infarction as an inevitable and essentially untreatable pathologic event. I have attempted to outline current methods for characterization of the ischemic process by regional metabolism since it appears evident that such definition will prove of both diagnostic and prognostic value. Unfortunately, as old problems are solved new

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ones continue to appear. We are still baffled by the high incidence of myocardial infarction occurring at rest in previously asymptomatic patients and in some few patients with normal coronary arteries. The pathogenesis of the so-called Prinzmetal angina remains an enigma as does the true relation between

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angina pectoris and myocardial infarction. Are these two separate diseases or different limbs of the same tree? Finally, many of us continue to wonder if there is any adaptation to chronic ischemia or indeed if ischemia can exist on a long-term basis without evolving into myocardial infarction.

References 1. Btng RJ, Vandam LD, Gregolre F, et al: Catheterization of coronary sinus and middle cardiac vein in man. Proc Sot Exp Biol Med 66:239-240, 1947 2. Wollenberger A: The energy metabolism of the failing heart and the metabolic action of the cardiac glycosides. Pharmacol Rev I:31 l-352, 1949 3. Olson RE: Myocardial metabolism in congestive heart failure. J Chronic Dis 9:442-464, 1959 4. Jennings RB: Myocardial ischemia: observations, definitions and speculations. J Mol Cell Cardiol 1:345-349, 1970 5. Jennings RB, Ganote CE, Reimer KA: lschemic tissue injury. Am J Pathol 81:179-198, 1975 6. Karlsson J, Templeton GH, Willerson JT: Relationship between epicardial S-T segment changes and myocardial metabolism during acute coronary insufficiency. Circ Res 32:725-730, 1973 7. Griggs DM, Tchokoev VV, Chen CC: Transmural differences in ventricular tissue substrate levels due to coronary constriction. Am J Physiol 222:705-709, 1972 8. Jennings RB, Sommers HM, Smyth GA, et al: Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol 70:68-78, 1960 9. Jennings RB, Reimer KA: Salvage of ischemic myocardium. Mod Concepts Cardiovasc Dis 43: 125-130, 1974 10. Alonzo DR, Scheidt S, Post M, et al: Pathophysiology of cardiogenie shock. Circulation 48:588-596, 1973 11. Herman MV, Elliott WC, Gorlin R: An electrocardiographic, anatomic and metabolic study of zonal myocardial ischemia in coronary heart disease. Circulation 35:834-846, 1967 12. Obeid A, Smulyan H, Gilbert R, et al: Regional metabolic changes in the myocardium following coronary artery ligation in dogs. Am Heart J 83:189-196, 1972 13. Owen P, Thomas M, Young V, et al: Comparison between metabolic changes in local venous and coronary sinus blood after acute experimental coronary artery occlusion. Am J Cardiol 25~562-570, 1970 14. Corday E, Lang T, Meerbaum S, et al: Closed chest model of intracoronary occlusion for study of regional cardiac function. Am J Cardiol 33:49-59, 1974 15. Hoffstein S, Gennaro DE, Fox AC, et al: Colloidal lanthanum as a marker for impaired plasma membrane permeability in ischemit dog myocardium. Am J Pathol 79:207-218, 1975 16. Opie, L: Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction. Am J Cardiol 36:938953, 1975

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Brachfeld N: lschemic myocardial metabolism and cell necrosis. Bull NY Acad Med 50:261-293, 1974 Most AS, Gorlin R, Soeldner JS: Glucose extraction by the human myocardium during pacing stress. Circulation 4592-96. 1972 Brachfeld N, Keller N, Tarjan E, et al: Myocardial metabolism following pacing induced stress (abstr). Circulation 44 Suppl II: n-145, 1971 Opie L, Owen P, Thomas M, et al: Coronary sinus lactate measurements in assessment of myocardial ischemia. Am J Cardiol 32:295-305, 1973 Gorlin R: Assessment of hypoxia in the human heart. Cardiology 57124-34, 1972 Henderson AH, Craig RJ, Gorlin R, et al: Lactate and pyruvate kinetics in isolated perfused rat hearts. Am J Physiol 217: 1752-1756, 1969 Scheuer J, Berry MN: Effect of alkalosis on glycolysis in the isolated rat heart. Am J Physiol 213:1143-l 148, 1967 Huckabee WE: Relationship of pyruvate and lactate during anaerobic metabolism. J Clin Invest 37:244-263, 1958 Neely JR, Denton RM, England PJ, et al: The effects of increased heart work on the tricarboxylic acid cycle and its interactions with glycolysis in the perfused rat heart. Biochem J 128:147-159, 1972 Kuhn P, Pachinger 0: The effect of calcium on myocardial lactate production under aerobic conditions. J Mol Cell Cardiol 4: 171-174, 1972 Parker JO, Chiong MA, West RO, et al: The effect of ischemia and alterations of heart rate on myocardial potassium balance in man. Circulation 42:205-217, 1970 Opie LH, Thomas M, Owen P, et al: Increased coronary venous inorganic phosphate concentrations during experimental myocardial infarction. Am J Cardiol 30:503-513, 1972 Fox AC, Reed GE, Glassman E, et al: Release of adenosine from human hearts during angina induced by rapid atrial pacing. J Clin Invest 53:1447-1457, 1974 Berger HJ, Zaret BL, Speroff L, et al: Cardiac prostaglandin release during myocardial ischemia induced by atrial pacing in patients with coronary artery disease, in press Pitt B, Mason J, Contt CR: Observations on the plasma kallikrein system during myocardial ischemia. Trans Assoc Am Physicians 82:98-108, 1969 Mills RM, Mudge GH, Taegtmeyer H, el al: Alterations of myocardial amino acid metabolism in coronary artery disease (abstr). Circulation 51. 52: Suppl ll:ll-90, 1975

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