AN IMPROVED METHOD FOR MEASURING THE SIZE OF MYOCARDIAL INFARCTIONS A. S. SLUTSKY, McMaster University Medical Centre, c/o Medical Education Office, 1200 Main Street West, Hamilton, Ontario, Canada. L8S 459.

SUMMARY A new method is proposed for the estimation of infarction size from several measurements of creatine phosphokinase (CPK) activity. This method develops the previous method of Shell and co-workers by introducing the concept of a time- dependent fractional disappearance rate for CPK (kd”‘)) from the blood. This method would allow more accurate estimates to be made of infarction size.

INTRODUCTION Damage due to myocardial infarction remains a major source of morbidity and mortality in the Western world. One of the most trying problems confronting clinicians and a question frequently asked by patients in a coronary care service is the extent of damage to the myocardium following an infarct. An estimate of the extent of damage is important for assessing prognosis as well as for evaluating the benefits of various pharmacological interventions. Indirect evidence of damage can be obtained at the bedside by estimating the presence and degree of shock as well as the severity of cardiac failure. These methods are largely qualitative rather than quantitative in nature. Of the more quantitative tools, “mapping” of the precordium with electrodes and subsequent analysis of the ST-segment changes is being studied (1, 2). This method gives valuable evidence of change in infarct size in patients whose STsegment elevations are solely due to an acute ischemic injury secondary to acute myocardial infarction, but

cannot be used in patients with ST-segment changes due in part to electrolyte imbalance, bundle-branch block, pericarditis and other factors (3). Furthermore, it does not provide an absolute value of the size of the infarction (3). Of the newer methods of estimating infarct size, isotope scanning of the myocardium holds promise, but it is at the present time relatively untested. By far the most widely used indirect method has been the study of serum enzymes. The most commonly used enzymes are creatine phophokinase (CPK), serum glutamic oxalacetic transaminase (SGOT) and lactic dehydrogenase (LDH) (4, 5). The time course for the appearance of these enzymes in the blood is shown in Figure I. The most widely studied enzyme in this group as an indicator of myocardial cell damage appears to be CPK (5, 6) mainly because it is to a large extent confined to cardiac muscle, skeletal muscle and brain. Very little is found in liver or kidney, organs which are often secondarily damaged following a myocardial infarct. The level of

Figure 1

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CELL MEDIATED IMMUNITY IN INTERMEDIATE ENVIRONMENTS blood can be considered as being injected into the blood as a function of time (=@)), rather than as a bolus. The area of the concentration curve under f(t) times the distribution space of CPK will represent the total amount of CPK that is injected into the blood. The level of CPK in the blood, (E(t)), can then be considered as a resultant of two com~ting phenomena: 1. CPK is being added to the blood according to the injection function f(t) 2. CPK concentration in the blood is decaying with a rate constant kd i.e. the rate of decay of serum CPK at any given time will equal the rate constant times the concen~ation of CPK at that time, (kd x E(t)). In attempting to estimate infarct size, however, we cannot measure CPKr, CPKd or f(t) directly because at any point in time there are a number of competing phenomena proceeding. We can measure only the result of these steps, that is, FE(t).i Shell’s model takes the variable that we can measure, E(t), and mathematic~ly retraces each step to determine Kt) and CPKd to arrive at a value of the amount of CPK released from damaged mycardium, (CPK,). It has been shown that this value, CPKI, can be used to estimate infarct size (8). Figure 3 shows the same scheme as figure 2, but drawn this time from right to left giving each of the equations used to arrive at infarct size. A full description of each equation is given below:

circulating CPK in venous blood represents an interplay between the amount released and the amount metabolised. The level of serum CPK at any given time is thus influenced by the time course of the myocardial infarction. Indeed it is sometimes difficult to be certain at which time the infarct first occurred. If the dynamics of CPK appearance and the disappearance from the blood and the relationship between total CPK release and extent of damage could be worked out, we would have a valuable tool for the quantification of infarct size. Shell et al (7), have contributed greatly in this area with their model of estimating infarct size from serum CPK values. There are, however, some practical limitations to their approach. For example, in the estimate of CPK dynamics, several assumptions are made concerning the size of the distribution space, the fraction of CPK released from the myocardium appearing in the blood following an infarct and the fractional disappearance rate of CPK from the blood. It is unlikely that these assumptions are completely valid as there is considerable variation both within and among subjects, especially in the fractional disappearance rate. As a first step in improving the clinical application of such an approach, it seemed of value to develop a form of analysis which avoided the major assumptions made by Shell’s approach. This paper is directed towards describing an alternate approach which, if clinically applicable, may in the future greatly improve the estimation of myocardial infarct size.

(1)- dJ3t) = @t)+ [kdx E(t)]

dt This equation describes the fact that the rate of change of enzyme activity (dE(t)/dt) depends on two competing phenomena: 1. f(t) = release of enzyme into the circulation (in concentration units) 2. kd x E(t) = clearance of enzyme (kd as defined is always a negative quantity.)

THE INFARCT

SIZE MODEL OF SHELL AND CO-WORKERS A schematic diagram of Shell’s model outlining the various assumptions from the release of CPK from infarcted tissue to the appearance of the CPK curve, E(t), is shown in Figure 2. A certain mount of CPK is released from infarcted tissue (=CPKd), depending on the extent of damage. Only a fraction of this released CPK eventually appears in the blood (=CPKJ, presumably because a considerable percentage of the CPK is metabolised before it enters the blood. The amount of CPK that appears in the

(II) CPK, = J;

fU)dt x [CPK,,l

This equation states that the total amount of CPK released into the circulation is the integral of the enzyme 179

Figure 3

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interventions will adversely influence the use of calculated infarct size as a prognostic tool and as a tool for evaluating various therapeutic interventions. This paper describes an improved method for estimating kd as a function of time, (kd\(t)),lduring the immediate post-infarct period such that more accurate estimates of infarct size may be obtained.

CPKd= CPK,/D

This equation states that only a certain fraction of CPK released from the myocardium gets into the circulation. This constant, D, was determined empirically.

THE SUGGESTED IMPROVEMENT Since kd is not a constant but varies with many factors which themselves vary with time, fractional disappearance rate is assumed to be a function, (kd((t)),[that varies with time. To calculate this time-varying function’kd((t) the following methodology is proposed: 1. Inject a small bolus of labelled CPK into the subject as soon after the occlusion as possible. 2. Determine the concentration of total serum CPK values (E(t)) and the concentration of labelled CPK (call it L(t)) at varying time intervals (call the time at which the injection was made t = 0). 3. Now, using the same model as before:

CPK, (IV) Infarct size = (CPK,) (CPK,) The denominator of this equation gives the difference (calculated from a number of experiments) between the concentration of CPK in normal myocardium and the centre of infarcted myocardium. Thus, the ratio CPK&’ [(CPK,) - (CPKi)l gives the estimated infarct size. The estimate of myocardial infarct size using this model is directly dependent on the value of the decay constant ka Shell et al assume that kd is a constant. They measure the value of the constant by injecting partially purified CPK into conscious dogs. The changes in serum CPK activity after injection show a biphasic pattern. There is an initial decay representing dilution followed by a monoexponential decay: kd is the decay constant of this exponential. The parameter kq however, varies from animal to animal and varies even within the same animal during various pharmacological interventions and during pathophysiological phenomena, such as decreased cardiac output. The variation of kd during the post-infarction period is unknown. However, Shell et al have conducted experiments in which a drop in cardiac output of about 20-25% resulted in a change in average kd from-O.0048 to -0.0070 (7). Using the mean value of -0.0048 for kd in calculating infarct size could result in an error in estimating infarct size of approximately 30%. Similarly, with isoproterenol administration the average kd was -0.0090 which would produce an error in estimated infarct size of approximately 45%. In patients with acute myocardial infarction, it is likely that pathophysiologic changes and pharmacological

-

dE(t) dt

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f(t)

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[Ikd’(t)+ E(t)]

In this equation the disappearance rate is a function of time. 4. Assuming the labelled CPK is uniformly distributed and using an analogous model: -

dut) dt

=

kd(t) x E(t)

In this case there is no “f(t)” because there is no more labelled CPK that is being injected after the original bolus. Therefore, Mt) = (dL(t)/dt)/E(t) We know the function of L(t) and E(t) and can therefore calculate dL(t)/dt. CONCLUSIONS It has been shown that prognosis following a myocardial infarction is related to the size of the infarct (7) and that the 180

FREQUENCY OF NEOPLASIA AT DIFFERENT LEVELS OF T CELL FUNCTION FOR A STANDARD TIME/SEVERITY STIMULUS

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size of an infarct following coronary occlusion may be reduced by various interventions (9-12). The validity of these potentially important observations is dependent on the av~a~~ty of an accurate method of measu~ng infarct size. This paper proposes a method for improving the application of the model introduced by Shell et al in the assessment of the extent of myocardial infarction by analysing serial changes in serum creatine phosphokinase activity. The improvement proposed concerns the determination of a parameter, the fractional disap~~~ce rate of CPK, which Shell et al assume to be constant for any given-subject. This paper proposes that the fractional disappearance rate should be viewed as a time dependent variable (kd((t))and a method is described for estimating this function during the immediate post infarctional period even when the CPK appearance function (r(t)) is not equal to zero. Once k&)jhas been determined as described, the total amount of CPK released into the blood stream can then be calculated using the follawing formula:

In conclusion, the proposed method of estimating infarct size eliminates one of the major problems of the model of Shell et al and might allow the influence and efficacy of various ph~acologic~ inte~entions to be more accurately determined during the critical post-infarction phase. Acknowledgments I would like to thank Dr. P. Maroko and Dr. E. Braunw~d from the Department of Medicine, Peter Bent Brigham Hospital, Boston, Massachusetts, for the opportunity of working in their laboratory and for the introduction to the problem of modifying the extent of myocardial infarction. I would also like to thank Dr. A. S. Rebuck of McMaster University, Hamilton, Ontario for his generous help in the preparation of this paper.

REFERENCES 1.

Maroko P R, Kjekshus J K, Sobel B I?, Watanabe T, Covell J W, Ross J Jr, Braunw~d E, Factors inthmncin infarct size following experimental coronary artery occlusions. nitration, 43, 67-82,

2.

Maroko wald E, method ils;smic

3.

Mardko P R, Assessing myocardial damage in acute infarcts. New England Journal of Medicine, 290, 158-159, 1974. Kibe 0, Nilsson N J, Observations on the diagnostic and prognostic value of some enzyme tests in myoeardial infarction. Acta Medica Scandinavica, 182, 597-610, 1967. Kluge W F, Prognostic value of serum creatinephosphokinase levels in myocardial infarction. Northwest Medicine, 6% 847,1969. Sobel B E, Breanahan G F, Shell W E, Yoder R D, Estimation of infarct size and its relation to prognosis. Circulation, 46, 640648, 1972. Shell W E, Kjekshus J K, Sobel B E, Qu~titative assessment of the extent of myocardial infarction in the conscious dog by means of analysis of serial changes in serum creatine phosphokinase activity. Journal of Clinical Investigation, 50, 2614-2625, 1971. Kjekshus J K, Sobel B E, Depressed myocardtal creatine phosphokinase activity following experimental myocardial infarction in rabbit. Circulation Research, 27, 504-414, 1970. Maroko P, Braunwald E, Modification of myocardiai infarction size after coronary ~clus~on. Annals ~lntern~ Medicine, 79,72@733, 1973. Libby P, Maroko P R, Cove& J W, Malloch C I, Ross J Jr, Braunwald E, Effect of protocol on the extent of myocardial rschemic injury after experimental coronary occlusion and its effects on ventricular function in the normal and ischemic heart. Cardiovascular Research, 7, 167-173, 1973. Shell W E, Sobei B E, Protection of jeopardized ischemic myocardium by reduction of ventricular afterload. New England Journal of Medicine, 291, 481-486, 1974. Braunwald E, Maroko P R, Libby P, Reduction of infarct size followina coronary occlusion. Circulation Research, 35, 192-201, 1974. Chawla A S, Chang ‘I’ M S, Non-thrombogenic surfaces by radiation grafting of heparin. In-vitro and in vivo studies. Biomaterials, Medical Devices and Artificial Organs, 2, 157, 1974.

1971._. -_

The application of this method in estimating infarct size is complicated by the contribution to serum CPK from non-myoc~di~ sources. This problem can be solved by &enzyme of creatine using the myoc~di~-spec~c phosphokinase (MB form). Another possible limitation to this improved method is the fact that in estimating kd (t) a foreign protein must be injected into the patient. This is not a problem in evaluating various interventions in animals but might be so in using this method in humans. However, there are many tests, such as leg scanning for thromboemboli and liver scanning which depend on the injection of a foreign protein. Recently a method has been developed (13) for the synthesis of thin, spherical, semipermeable membranes which can be prepared in such a way that they include aqueous solutions or sus~nsions of proteins and enzymes. Small substrate molecules can enter the capsules, The capsules, if prepared with labelled CPK, would then decay with the same dynamics as any CPK injected intravenously. These semipermeable capsules have been shown to be non-thrombogenic and non-antigenic. However, this method of using CPK in micro~aps~es has not been tested and it remains to be seen whether the benefits which might be derived from a more accur,ate estimate of infarct size outweigh the possible deleterious effects.

4. 5. 6. 7.

8. 9. 10.

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P R, Libby P, Cove11J W, Sobel B E, Ross J Jr, BraunPrecordial S-T se ment elevation mapping: an atraumatic for measuring a!@rations in the extent of myocardial injury. American Journal of cardrology, 29, 223-230,

An improved method for measuring the size of myocardial infarctions.

AN IMPROVED METHOD FOR MEASURING THE SIZE OF MYOCARDIAL INFARCTIONS A. S. SLUTSKY, McMaster University Medical Centre, c/o Medical Education Office, 1...
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