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 4J9.
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 (t) from the blood. This method would allow more accurate estimates to be made of infarction size.
INTRODUCTION
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
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 Figure 1 c
2 a
TYPICAL
CHANGES IN SERUM ENZYMES TIME AFTER INFARCT CPK
I 1
I 2
I 3
I 4
I 5
I I I I 6789101112
I
I
INFARCT
5
DAYS
AFTER
MYOCARDIAL 217
INFARCT
VS
1)
Figure 2
SCHEMATIC OF MODELTO ESTIMATE INFARCT SIZE
,,“i: f
infarcted area
-
Serum CPK values change
Some CPK
The CPK is injected
enters the
into the blood as a
vascular system
rate of disappearance of CPK
function of time
in the circulation
= f 81
E ftf = serum CPK values
= CPKr .~
depending on f tt\ and the (I$$
E tt)
size of the distribution space, the fraction of CPK released from the myocardium appearing in the blood foliowing an infarct and the fractional disappearance rate of CPK from the blood. It is unlikely that these assumptions are completeIy valid as there is considerabIe 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.
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 myocardi~ 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 nat provide an absolute value of the size of the infarction (3). Of the newer methods of estimating infarct size, isotope scanning of the myoc~dium 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 (SCOT) 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, skdetal muscle and brain. Very little is found in liver or kidney, organs which arc often secondarily damaged following a myocardial infarct. The level of 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 in~uenced by the time course of the myocardi~ 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 ~ua~ti~cation 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 Iimitations to their approach. For example, in the estimate of CPK dynamics. several assumptions are made concerning the
THE INFARCT
SIZE MODEL OF SHELL AND CO-WORKER§
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 amount of CPR is released from infarcted tissue (=CPKd), depending on the extent of damage. Only a fraction of this released CPK eventually appears in the blood (=CPKr), presumably because a considerable percentage of the CPK is metabolised before it enters the blood. The amount of CPK that appears in the blood can be considered as being injected into the blood as a function of time (=fTt)), rather than as a bolus. The area of the concentration curve under f@) times the dis~ibution 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 competing phenomena: 1. CPK is being added to the bfood 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 concentration of CPK at that time, fkd x E(t)).
218
MATHEMATICAL
Figure 3
MODEL TO ESTIMATE INFARCT SIZE
r-5erum
Constants
CPK
values
‘--(___.-D-_
introduced
at each step
II!. I k
Fractional d
Infarct
size
disappearance
rate of CPK
II. [CPKos]
--a =
--..-
CPK,,
[CPK.
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 4J9.
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 (t) from the blood. This method would allow more accurate estimates to be made of infarction size.
INTRODUCTION
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
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 Figure 1 c
2 a
TYPICAL
CHANGES IN SERUM ENZYMES TIME AFTER INFARCT CPK
I 1
I 2
I 3
I 4
I 5
I I I I 6789101112
I
I
INFARCT
5
DAYS
AFTER
MYOCARDIAL 217
INFARCT
VS
1)
Figure 2
SCHEMATIC OF MODELTO ESTIMATE INFARCT SIZE
,,“i: f
infarcted area
-
Serum CPK values change
Some CPK
The CPK is injected
enters the
into the blood as a
vascular system
rate of disappearance of CPK
function of time
in the circulation
= f 81
E ftf = serum CPK values
= CPKr .~
depending on f tt\ and the (I$$
E tt)
size of the distribution space, the fraction of CPK released from the myocardium appearing in the blood foliowing an infarct and the fractional disappearance rate of CPK from the blood. It is unlikely that these assumptions are completeIy valid as there is considerabIe 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.
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 myocardi~ 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 nat provide an absolute value of the size of the infarction (3). Of the newer methods of estimating infarct size, isotope scanning of the myoc~dium 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 (SCOT) 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, skdetal muscle and brain. Very little is found in liver or kidney, organs which arc often secondarily damaged following a myocardial infarct. The level of 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 in~uenced by the time course of the myocardi~ 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 ~ua~ti~cation 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 Iimitations to their approach. For example, in the estimate of CPK dynamics. several assumptions are made concerning the
THE INFARCT
SIZE MODEL OF SHELL AND CO-WORKER§
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 amount of CPR is released from infarcted tissue (=CPKd), depending on the extent of damage. Only a fraction of this released CPK eventually appears in the blood (=CPKr), presumably because a considerable percentage of the CPK is metabolised before it enters the blood. The amount of CPK that appears in the blood can be considered as being injected into the blood as a function of time (=fTt)), rather than as a bolus. The area of the concentration curve under f@) times the dis~ibution 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 competing phenomena: 1. CPK is being added to the bfood 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 concentration of CPK at that time, fkd x E(t)).
218
MATHEMATICAL
Figure 3
MODEL TO ESTIMATE INFARCT SIZE
r-5erum
Constants
CPK
values
‘--(___.-D-_
introduced
at each step
II!. I k
Fractional d
Infarct
size
disappearance
rate of CPK
II. [CPKos]
--a =
--..-
CPK,,
[CPK.
