Adv. Cardiol., vol. 23, pp. 14-24 (Karger, Basel 1978)
Clinical Pathologic Correlates in Acute Myocardial Infarction 1 COLIN M. BLOOR, WILLIAM R. ROESKE and ROBERT A. O'ROURKE Departments of Pathology and Medicine, UCSD School of Medicine, La Jolla, Calif.
1 This work was supported in part by MIRU Contract PH-43-68-1332 and the Specialized Center on Ischemic Heart Disease HL 17682 from NHLBI.
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Various approaches and protocols are now available for thorough examination of the postmortem heart in order to provide appropriate data for correlation with clinical parameters obtained in the same patients. Studies have been conducted under the MIRV and Ischemic Heart Disease SCOR programs of the National Institutes of Health since 1968. From these studies and others, a number of interesting clinical pathologic correlations have been made which can be useful in evaluating new approaches or interventions in patients with acute myocardial infarction. Patients entering these studies have a definite diagnosis of acute myocardial infarction based on the following clinical criteria: (1) classic history of prolonged chest pain; (2) characteristic serum enzyme elevation, and (3) evolutionary electrocardiographic changes of acute myocardial infarction. Before admission to the unit, 2 of the 3 criteria must be present. A variety of clinical observations have been obtained in these patients and the autopsy protocol has been designed to assess the accuracy and significance of the clinical findings. Major emphasis has been placed on the determination of myocardial infarct size and the extent and severity of coronary atherosclerosis. In this presentation, we will describe briefly the autopsy protocol and the characteristics of the autopsy population of patients dying from acute myocardial infarction. Then, interesting pathologic findings associated with arrhythmias in myocardial infarction and the effects of reperfusion will be discussed. Also, correlation between postmortem infarct size and other clinical data in the postmyocardial infarction patient will be presented.
Clinical Pathologic Correlates
15
Autopsy Protocol
Major emphasis has been placed on accurate determination of myocardial infarct size at autopsy of these patients and recording the severity and extent of coronary atherosclerosis for correlation with similar observations obtained by in vivo coronary angiography. The protocol is similar to the one described by HACKEL and RATLIFF [3]. After appropriate inflation and fixation of the heart, it is sectioned at i-cm thick levels from apex to base resulting in 5-6 blocks. Infarct size is then outlined and a record made of both location and the extent of old and new infarcts from gross features. Blocks are taken from selected sites for microscopic conformation of the gross observations. The infarct size is then planimetered and calculated as a percent of total ventricular mass. Various injection methods are available for outlining the coronary vascular bed. Vinylite plastic casting techniques have been used for many years but have the disadvantage that tissue must be digested to demonstrate the coronary vasculature. A modified Schlesinger mass, according to HALES and CARRINGTON [5], makes it possible to do postmortem angiograms on the heart. After recording the coronary lesions seen on the postmortem angiogram, appropriate blocks can be taken from coronary vessels according to ROBERTS and BUJA'S [7] technique for confirming extent and severity of the coronary disease. These observations can be recorded on forms similar to that used during in vivo coronary angiography. Data attained from such postmortem examinations of hearts can be recorded in an appropriate manner to facilitate correlation with clinical data obtained from the patients while alive.
One concern in the use of autopsy data is how representative these findings are of the general population of patients having acute myocardial infarction. We have had the opportunity to review a large group of patients with acute myocardial infarction and compare features available from history, physical examination and from noninvasive and invasive techniques in autopsied and non-autopsied patients. Certain distinguishing features of the autopsy population group of patients are apparent and any interpretation from autopsy findings should be regarded within these limits. Figure I shows the survival rate of patients with acute myocardial
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Autopsy Population
16
BLOOR/RoESKE/O'RoURKE 100
• All patients (n= 326) • Autopsied patients (n=B3) " Non-living patients(n=53)
;;"-
~
~ ~ 50
o
2
3
4-
5
6
Years
Fig. 1. Survival rate in patients with definite myocardial infarction. Expired patients have been subdivided into autopsy and no autopsy groups. 100
;;"-
~
";;
~
50
o
3
4-
5
6
Months =
83).
infarction in three categories, i.e. (1) all patients; (2) those dying and being autopsied, and (3) those dying but not being autopsied. It is evident that the autopsied patient group has a higher mortality rate in the very early phase of the disease. Those nonliving patients without autopsy survive for a longer time. Figure 2 shows the survival rate of the autopsy patients at monthly intervals and approximately 60 % died within the first 30 days of the onset of acute myocardial infarction. This is not unexpected since autopsy rates in
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Fig. 2. Survival rate in autopsied patient groups (n
Clinical Pathologic Correlates
17
Table I. Clinical parameters on history or physical examination Definite MI, expired autopsy (n = 83)
no autopsy (n = 52)
Definite MI, living (n = 187)
Previous MI
27 (33)
18 (35)
43 (23)
CHF
15 (18)
12 (23)
25 (13)
COPD
16 (19)
7 (13)
10 (5) *
Rales above scapula
14 (17)
7 (13)
8 (4)
*
MI = Myocardial infarction; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; percentages are given in parentheses. * p < 0.05 compared to autopsy group.
Table II. Clinical parameters on admission Definite MI, expired autopsy (n = 83) Age, years
no autopsy (n = 52)
Definite MI, living (n = 187)
*
62± 1
63±2
Sex, male/female
63/21
40/12
HR, beats/min
96±3
86±3 *
81 ± 1 *
114±3
130 ± 5 *
135 ± 2 *
Sys. BP, mm Hg
59 ±1 135/52
patients dying within the hospital are much higher than those obtained in patients who are discharged from the hospital and then die later at home or unattended. Thus, the autopsy population represents a group of patients that die very early in acute myocardial infarction. Tables I - IV compare various clinical parameters in those patients having myocardial infarction and still alive to those who have died whether autopsied or not. On history or physical examination (table I), significant differences were noted in the presence of chronic obstructive pulmonary disease and rales above the
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Values are means ± SEM. * P < 0.05 compared to autopsy group.
18
BLOOR/RoESKE/O'RoURKE
Table III. Clinical parameters by non-invasive methods Definite MI, expired autopsy (n = 83)
Definite MI, living
no autopsy (n = 52)
(n = 187)
ECG (lst 24 h)
30 HB VF
13 (16)
4 (8)
8 (4) *
8 (10)
4 (8)
9 (5)"
Stach.
40 (48)
15 (29) *
43 (23) *
SV tach.
38 (27)
9(17)*
37 (20) *
LHD
54± 1
52± 1
49± 1 *
Infarct size
6.5 ±0.3
5.4±0.3 *
4.8 ±0.1"
30 HB = Third degree heart block; VF = ventricular fibrillation; Stach. = sinus tachycardia; SV tach. = supraventricular tachycardia; LHD = left heart dimension on chest film; infarct size = infarct size from serial CPK curves; percentages are given in parentheses. * p < 0.05 compared to autopsy group.
Table IV. Clinical parameters by invasive methods Definite MI, expired
Definite MI, living
autopsy (n = 83)
no autopsy (n = 52)
CI
2.2±0.2
2.S±0.2
SVI
22±2
28±2*
A-V02 diff.
6.5 ±0.3
5.4 ± 0.3
20.2
17.4
LV filling pressure
(n = 187)
2.6 ±0.1
*
32± 1 *
*
4.8 ± 0.1
*
13.3
.. p < 0.05 compared to autopsy group.
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Values are means ± SEM. CI = Cardiac index; SVI = stroke volume index; A-V02 diff. = arteriovenous oxygen difference; LV filling pressure = left ventricular filling pressure .
Clinical Pathologic Correlates
19
scapulae which were significantly increased in the autopsy population group. On admission to the study, the autopsy group of patients were slightly older, had a higher heart rate, and a lower systolic blood pressure (table II). There were no significant differences between the groups in the ratio of males to females; however, the disease was more prevalent in males. In looking at noninvasive data, significant differences between the autopsy population and the other two groups were noted with respect to a higher frequency of 3rd degree heart block, ventricular fibrillation, sinus tachycardia, and supraventricular tachycardia. The radiographic left heart dimension was larger in the autopsy population. The infarct size determined by completed CPK enzyme curves was significantly greater in the autopsy population group. Finally, invasive measurements recorded in the patients (table IV) showed a significant reduction in both cardiac index and stroke volume index, and a significant increase in A V02 difference and left ventricular filling pressure in the autopsy population group. In general, patients with acute myocardial infarction dying and coming to autopsy are sicker individuals by clinical criteria as one might expect. Thus, when relating autopsy data back to the general population of patients with acute myocardial infarction, one must remember that they are a slightly skewed population with more severe aspects of the disease.
Interesting clinical-pathologic correlations occur in patients with acute myocardial infarction and various types of arrhythmias. When intraventricular conduction defects are present, the myocardial infarcts usually are small, focal, and patchy. No large coalescing lesions are seen. When the infarct becomes extensive and coalesces in the interventricular septum, hemiblock may occur. When the infarct is very extensive and occupies two thirds or more of the interventricular septum, left bundle branch block is present in the patients. HACKEL et al. [4], have reported the anatomic features present in 12 patients with acute myocardial infarction in whom detailed studies of the conduction system were undertaken. These patients had various forms of atrioventricular block, left bundle branch block, and right bundle branch block. Of interest was that 6 of the 12 patients had focal necrosis of the conducting fibers when atrioventricular block was present; however, another 6 patients with atrioventricular block had intact conduction fibers and only an adjacent infarct. In those patients with left bundle branch block, 2 had no
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Arrhythmias
20
evidence of necrosis of the conduction system, but an adjacent infarct. In those patients with right bundle branch block, 3 had an adjacent infarct, none had evidence of focal necrosis and in 1 no lesion was seen. Some conduction defects may be transient in patients with acute myocardial infarction and thus one might not anticipate a specific lesion or focus of necrosis in the conducting fibers. The mechnisms suggested by HACKEL et al. [4], for the origin of transient conduction defects include: (1) altered ionic environment; (2) sublethal ischemia; (3) infiltrated leukocytes, and (4) vagal reflexes. Since potassium leaks from the necrotic tissue, it may alter the function of conduction tissue, if the infarct is adjacent to conducting fibers. Evidence for this has been shown by UOELNOV [10] who excised necrotic muscle from a dog heart, placed it on a normal dog heart and showed arrhythmia induction. In sublethal ischemia, there can be an influx of sodium and efflux of potassium from the conducting fiber with loss of membrane resting potential. But the severity of this is not sufficient to induce tissue necrosis since arrhythmias frequently occur at the time when leukocytic infiltrate is maximal in the tissue and release of lysosomal enzymes may also have an effect on conducting tissue. The explanations offered for conduction fiber sparing in acute myocardial infarction include: (1) separate blood supply; (2) direct oxygen diffusion, and (3) metabolic differences. Although separate blood supply to the conduction system has been proposed, there is no evidence to support this. The blood supply to the conducting tissue is similar to that which is interrupted when acute myocardial infarction ensues. So, this is an unlikely explanation. Since the major parts of the conduction system lie close to the endocardial surface, direct oxygen diffusion may occur from the ventricular chambers and suffice to maintain viability of the conduction tissue. HACKEL et al. [4], have reported a case in which focal necrosis of the right bundle was localized to the site furthest away from the right ventricular chamber supporting such an explanation. In addition, conduction tissue has certain metabolic differences from normal myocardium. The conduction fibers have a higher glycogen content and their oxygen consumption is less; thus, under anaerobic conditions, their higher glycogen content may have enabled them to survive for a longer time. SCRIEBLER et al. [8] showed the oxygen consumption of conduction fibers in the myocardium to be 20% of values obtained from normal myocardial fibers. This relates to the difference in contractile activity of the other fibers. Thus, under hypoxic conditions, the oxygen demand of conduction tissue may still be met by the low flow levels present.
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BLOOR/RoESKE/O'RoURKE
Clinical Pathologic Correlates
21
Reperfusion
When the myocardium is reperfused after coronary occlusion, certain changes in the flow response may occur that affect infarct size. The ability of the coronary vascular bed to dilate and flow during reperfusion is partly dependent on the duration of the occlusion. BLOOR and WHITE [2] have shown that if occlusion is greater than 6 h, a significant decrease in the functional capacity of the coronary bed occurs on reperfusion, and may require 4-5 days before it recovers to the normal level. This influences the ensuing infarct size, namely the longer recovery time for coronary vascular capacity to return to control levels, the larger the infarct size. In addition, regional changes in flow distribution after coronary artery occlusion also occur. BISHOP et al. [1] showed a central core zone in large infarcts in which flow decreased at the onset of occlusion to about 10% of control level and, after 4 or 5 days, showed no change. The subendocardial zone, in particular, seems most vulnerable. Even though reperfusion is established early, most tissue in the endocardial zone becomes necrotic. Thus, any change in infarct size results from salvaging tissue in the marginal zone. Whether it is possible to salvage tissue from the endocardial region or central part of the infarct is not known.
The following correlations have been conducted in acute myocardial infarction patients. Figure 3 shows the relationship between old infarct and new infarct in this autopsied population group. Patients dying within 24 h or who died of non cardiac causes during the follow-up period have been excluded from this analysis. There is an inverse relationship between the extent of old infarct and the new infarct. This would be expected if patients died with equivalent hemodynamic embarrassment from infarct size and were not maintained by heroic measures while large new areas of infarction developed. It is interesting to note that the intercepts on the two axes are different. This suggests that the patients with prior myocardial infarcts died with total (old plus new) infarct sizes that were larger than patients who only had one infarct. Although a certain threshold of infarct size seems to be a major determinant of mortality in the disease, the latter feature suggests that some compensation may occur in the postmyocardial infarction patient who tends to have larger infarct size before death occurs.
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Clinical-Pathologic Correlations in Myocardial Infarction Patients
22
BLOOR/RoESKE/O'RoURKE
20
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....
.c
01
r=-O 80
~
.....
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.c
10
-
~
..... ~
~ ~ ~
Ql
Z
10
20
30
•
40
Old Infarct, '10 heart weight
We studied the relationship between the extent of vessel involvement in the 4 major coronary arteries, namely the left main, left anterior descending, left circumflex, and right coronary arteries and the total infarct size as determined at autopsy. In 5 % of patients, none of the 4 major vessels had greater than 70 % occlusion. The possible etiologies for this include: (1) limitation of arteriography; (2) functional coronary constriction; (3) small vessel disease; (4) platelet aggregation; (5) abnormal hemoglobin, and (6) redistribution of coronary flow. Of these possible etiologies, functional coronary constriction, platelet aggregation, and redistribution of coronary flow may occur when the individual is subjected to extreme flow seem the most likely. Even when coronary atherosclerosis results in less than 70 % constriction of the vessel, significant redistribution of coronary stress, and thus render the endocardial region more vulnerable to ischemic injury. In general, involvement of I or 2 coronary vessels resulted in intermediate degrees of infarct size noted at autopsy while when 3 of the 4 major coronaries had greater than 70 % occlusion, infarct size at time of death averaged 23 %. Analysis of variance showed statistical significance (p < 0.05), indicating that the total infarct size is highly dependent on the extent of coronary atherosclerosis. Next, we determined the relation between infarct size and a history of a prior myocardial infarct. Although some patients without a history of
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Fig. 3. Relation between new and old infarcts (expressed as a percentage of heart weight) as determined at autopsy.
Clinical Pathologic Correlates
23
myocardial infarction had a significant amount of old infarct noted at autopsy, there was a considerable number of old infarcts present in those patients who had a positive history. It is also interesting to note that patients with previous myocardial infarction died with less new infarct than did those patients without a positive history. This supports the concept that there is a threshold level of infarct which can be tolerated before a patient dies of hemodynamic embarrassment. The fact that the total infarct size is greater in those patients having a history of prior myocardial infarction suggests that some degree of compensation occurred in those patients. VAN TAssEL and EDWARDS [9] report myocardial rupture to occur in approximately 5 % of autopsy patients with acute myocardial infarction. It is usually seen in older individuals and is most frequent within the first week of the onset of acute myocardial infarction. Interestingly, NAEIM et af. [6] report that hearts of individuals with acute myocardial infarction resulting in rupture weigh less than those of patients with acute myocardial infarction without rupture. This suggests that compensatory hypertrophy may be beneficial in reducing the incidence of rupture. In our study, 7 patients with left ventricular rupture had a new infarct size of 16 % while 30 patients without ventricular rupture had an infarct size of 8 % which was significantly different (p < 0.05). In 5 patients with septal rupture, there was a greater amount of new infarct compared to the group who did not have septal rupture. Finally, we determined the amount of old and new infarct in patients having left ventricular aneurysm at autopsy. In contrast to the 2 groups of patients with left ventricular rupture and septal rupture, patients with aneurysms had significantly more old infarct documented and had the highest group average of any selected group of patients with old myocardial infarct size. These patients also died with the smallest additional amount of new myocardial infarct. The amount of new infarct was significantly less than the new infarct size seen in remaining patients.
In this patient population representing all patients dying after myocardial infarction who had infarct size determined at autopsy, there was a lack of correlation between infarct size and a variety of clinical data including heart rates, systolic blood pressure or radiographic heart size at the time of admission. Furthermore, the MIRV class on admission (class I-IV) did not correlate significantly with the extent of infarct at the time of autopsy. In contrast to the lack of correlation from any clinical variables, we concluded
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Summary
BLOOR/RoESKE/O'RoURKE
24
that total (old plus new) infarct size at autopsy was indeed related to the extent of coronary atherosclerosis present at autopsy. Patients with a history of prior myocardial infarction or with left ventricular aneurysms died with a greater total (old plus new) infarct size. These data suggest that a larger total infarct is necessary to produce mortality in patients who have compensatory changes from an old infarct. The patients expiring with only a new infarct frequently have the complications of left ventricular or septal rupture. These patients died with infarct sizes which averaged 15 % of left ventricular mass. The use of autopsy infarct size provides an important tool for validation of many methods that are currently involved in reducing infarct size, determined in vivo. These data suggest that infarct size correlates most highly with the extent of coronary atherosclerosis and not with the clinical variables associated with poor prognosis in an unselected population of postmyocardial infarction patients.
References
2 3 4
5 6 7
8 9
10
BISHOP, S. P.; WHITE, F. C., and BLOOR, C. M.: Regional myocardial blood flow during acute myocardial infarction in the conscious dog. Circulation Res. 38: 429-438 (1976). BLOOR, C. M. and WHITE, F. C.: Coronary artery reperfusion: effects of occlusion duration on reactive hyperemia responses. Basic Res. Cardiol. 70: 148-158 (1975). HACKEL, D. B. and RATLIFF, M. B.: A technique to estimate the quantity of infarcted myocardium post-mortem. Am. 1. clin. Path. 61: 242-246 (1974). HACKEL, D. B.; WAGNER, 0.; RATLIFF, N. B.; CIES, A., and ESTES, E. H., jr.: Anatomic studies of the cardiac conducting system in acute myocardial infarction. Am. Heart 1. 83: 77-81 (1972). HALES, M. R. and CARRINGTON, C. B.: A pigmented gelatin mass for vascular injection. Yale 1. BioI. Med. 43: 257-270 (1971). NAEIM, F.; MAZA, L. M. DE LA, and ROBBINS, S. L.: Cardiac rupture during myocardial infarction. A review of 44 cases. Circulation 45: 1231-1239 (1972). ROBERTS, W. C. and BUJA, L. M.: The frequency and significance of coronary arterial thrombi and other observations in fatal acute myocardial infarction: a study of 107 necropsy patients. Am. J. Med. 52: 425-443 (1972). SCHLIEBLER, T. H.; STARK, M. und CAESAR, R.: Die Stoffwechselsituation des Reizleitungssystems. Klin. Wschr. 34: 181-183 (1956). TASSEL, R. A. VAN and EDWARDS, J. E.: Rupture of heart complicating myocardial infarction: analysis of 40 cases including nine examples of left ventricular false aneurysm. Chest 61: 104-116 (1972). UDELNOV, M. 0.: The role of necrosis in the origin of electrocardiographic alterations characteristic of myocardial infarction. Circulation 24: 110--122 (1961).
Dr. C. M. BLOOR, Departments of Pathology and Medicine, UCSD School of Medicine, La Jolla, CA 92093 (USA)
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2
Clinical Pathologic Correlates in Acute Myocardial Infarction 1 COLIN M. BLOOR, WILLIAM R. ROESKE and ROBERT A. O'ROURKE Departments of Pathology and Medicine, UCSD School of Medicine, La Jolla, Calif.
1 This work was supported in part by MIRU Contract PH-43-68-1332 and the Specialized Center on Ischemic Heart Disease HL 17682 from NHLBI.
Downloaded by: University of Cambridge 131.111.164.128 - 3/19/2019 3:41:48 PM
Various approaches and protocols are now available for thorough examination of the postmortem heart in order to provide appropriate data for correlation with clinical parameters obtained in the same patients. Studies have been conducted under the MIRV and Ischemic Heart Disease SCOR programs of the National Institutes of Health since 1968. From these studies and others, a number of interesting clinical pathologic correlations have been made which can be useful in evaluating new approaches or interventions in patients with acute myocardial infarction. Patients entering these studies have a definite diagnosis of acute myocardial infarction based on the following clinical criteria: (1) classic history of prolonged chest pain; (2) characteristic serum enzyme elevation, and (3) evolutionary electrocardiographic changes of acute myocardial infarction. Before admission to the unit, 2 of the 3 criteria must be present. A variety of clinical observations have been obtained in these patients and the autopsy protocol has been designed to assess the accuracy and significance of the clinical findings. Major emphasis has been placed on the determination of myocardial infarct size and the extent and severity of coronary atherosclerosis. In this presentation, we will describe briefly the autopsy protocol and the characteristics of the autopsy population of patients dying from acute myocardial infarction. Then, interesting pathologic findings associated with arrhythmias in myocardial infarction and the effects of reperfusion will be discussed. Also, correlation between postmortem infarct size and other clinical data in the postmyocardial infarction patient will be presented.
Clinical Pathologic Correlates
15
Autopsy Protocol
Major emphasis has been placed on accurate determination of myocardial infarct size at autopsy of these patients and recording the severity and extent of coronary atherosclerosis for correlation with similar observations obtained by in vivo coronary angiography. The protocol is similar to the one described by HACKEL and RATLIFF [3]. After appropriate inflation and fixation of the heart, it is sectioned at i-cm thick levels from apex to base resulting in 5-6 blocks. Infarct size is then outlined and a record made of both location and the extent of old and new infarcts from gross features. Blocks are taken from selected sites for microscopic conformation of the gross observations. The infarct size is then planimetered and calculated as a percent of total ventricular mass. Various injection methods are available for outlining the coronary vascular bed. Vinylite plastic casting techniques have been used for many years but have the disadvantage that tissue must be digested to demonstrate the coronary vasculature. A modified Schlesinger mass, according to HALES and CARRINGTON [5], makes it possible to do postmortem angiograms on the heart. After recording the coronary lesions seen on the postmortem angiogram, appropriate blocks can be taken from coronary vessels according to ROBERTS and BUJA'S [7] technique for confirming extent and severity of the coronary disease. These observations can be recorded on forms similar to that used during in vivo coronary angiography. Data attained from such postmortem examinations of hearts can be recorded in an appropriate manner to facilitate correlation with clinical data obtained from the patients while alive.
One concern in the use of autopsy data is how representative these findings are of the general population of patients having acute myocardial infarction. We have had the opportunity to review a large group of patients with acute myocardial infarction and compare features available from history, physical examination and from noninvasive and invasive techniques in autopsied and non-autopsied patients. Certain distinguishing features of the autopsy population group of patients are apparent and any interpretation from autopsy findings should be regarded within these limits. Figure I shows the survival rate of patients with acute myocardial
Downloaded by: University of Cambridge 131.111.164.128 - 3/19/2019 3:41:48 PM
Autopsy Population
16
BLOOR/RoESKE/O'RoURKE 100
• All patients (n= 326) • Autopsied patients (n=B3) " Non-living patients(n=53)
;;"-
~
~ ~ 50
o
2
3
4-
5
6
Years
Fig. 1. Survival rate in patients with definite myocardial infarction. Expired patients have been subdivided into autopsy and no autopsy groups. 100
;;"-
~
";;
~
50
o
3
4-
5
6
Months =
83).
infarction in three categories, i.e. (1) all patients; (2) those dying and being autopsied, and (3) those dying but not being autopsied. It is evident that the autopsied patient group has a higher mortality rate in the very early phase of the disease. Those nonliving patients without autopsy survive for a longer time. Figure 2 shows the survival rate of the autopsy patients at monthly intervals and approximately 60 % died within the first 30 days of the onset of acute myocardial infarction. This is not unexpected since autopsy rates in
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Fig. 2. Survival rate in autopsied patient groups (n
Clinical Pathologic Correlates
17
Table I. Clinical parameters on history or physical examination Definite MI, expired autopsy (n = 83)
no autopsy (n = 52)
Definite MI, living (n = 187)
Previous MI
27 (33)
18 (35)
43 (23)
CHF
15 (18)
12 (23)
25 (13)
COPD
16 (19)
7 (13)
10 (5) *
Rales above scapula
14 (17)
7 (13)
8 (4)
*
MI = Myocardial infarction; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; percentages are given in parentheses. * p < 0.05 compared to autopsy group.
Table II. Clinical parameters on admission Definite MI, expired autopsy (n = 83) Age, years
no autopsy (n = 52)
Definite MI, living (n = 187)
*
62± 1
63±2
Sex, male/female
63/21
40/12
HR, beats/min
96±3
86±3 *
81 ± 1 *
114±3
130 ± 5 *
135 ± 2 *
Sys. BP, mm Hg
59 ±1 135/52
patients dying within the hospital are much higher than those obtained in patients who are discharged from the hospital and then die later at home or unattended. Thus, the autopsy population represents a group of patients that die very early in acute myocardial infarction. Tables I - IV compare various clinical parameters in those patients having myocardial infarction and still alive to those who have died whether autopsied or not. On history or physical examination (table I), significant differences were noted in the presence of chronic obstructive pulmonary disease and rales above the
Downloaded by: University of Cambridge 131.111.164.128 - 3/19/2019 3:41:48 PM
Values are means ± SEM. * P < 0.05 compared to autopsy group.
18
BLOOR/RoESKE/O'RoURKE
Table III. Clinical parameters by non-invasive methods Definite MI, expired autopsy (n = 83)
Definite MI, living
no autopsy (n = 52)
(n = 187)
ECG (lst 24 h)
30 HB VF
13 (16)
4 (8)
8 (4) *
8 (10)
4 (8)
9 (5)"
Stach.
40 (48)
15 (29) *
43 (23) *
SV tach.
38 (27)
9(17)*
37 (20) *
LHD
54± 1
52± 1
49± 1 *
Infarct size
6.5 ±0.3
5.4±0.3 *
4.8 ±0.1"
30 HB = Third degree heart block; VF = ventricular fibrillation; Stach. = sinus tachycardia; SV tach. = supraventricular tachycardia; LHD = left heart dimension on chest film; infarct size = infarct size from serial CPK curves; percentages are given in parentheses. * p < 0.05 compared to autopsy group.
Table IV. Clinical parameters by invasive methods Definite MI, expired
Definite MI, living
autopsy (n = 83)
no autopsy (n = 52)
CI
2.2±0.2
2.S±0.2
SVI
22±2
28±2*
A-V02 diff.
6.5 ±0.3
5.4 ± 0.3
20.2
17.4
LV filling pressure
(n = 187)
2.6 ±0.1
*
32± 1 *
*
4.8 ± 0.1
*
13.3
.. p < 0.05 compared to autopsy group.
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Values are means ± SEM. CI = Cardiac index; SVI = stroke volume index; A-V02 diff. = arteriovenous oxygen difference; LV filling pressure = left ventricular filling pressure .
Clinical Pathologic Correlates
19
scapulae which were significantly increased in the autopsy population group. On admission to the study, the autopsy group of patients were slightly older, had a higher heart rate, and a lower systolic blood pressure (table II). There were no significant differences between the groups in the ratio of males to females; however, the disease was more prevalent in males. In looking at noninvasive data, significant differences between the autopsy population and the other two groups were noted with respect to a higher frequency of 3rd degree heart block, ventricular fibrillation, sinus tachycardia, and supraventricular tachycardia. The radiographic left heart dimension was larger in the autopsy population. The infarct size determined by completed CPK enzyme curves was significantly greater in the autopsy population group. Finally, invasive measurements recorded in the patients (table IV) showed a significant reduction in both cardiac index and stroke volume index, and a significant increase in A V02 difference and left ventricular filling pressure in the autopsy population group. In general, patients with acute myocardial infarction dying and coming to autopsy are sicker individuals by clinical criteria as one might expect. Thus, when relating autopsy data back to the general population of patients with acute myocardial infarction, one must remember that they are a slightly skewed population with more severe aspects of the disease.
Interesting clinical-pathologic correlations occur in patients with acute myocardial infarction and various types of arrhythmias. When intraventricular conduction defects are present, the myocardial infarcts usually are small, focal, and patchy. No large coalescing lesions are seen. When the infarct becomes extensive and coalesces in the interventricular septum, hemiblock may occur. When the infarct is very extensive and occupies two thirds or more of the interventricular septum, left bundle branch block is present in the patients. HACKEL et al. [4], have reported the anatomic features present in 12 patients with acute myocardial infarction in whom detailed studies of the conduction system were undertaken. These patients had various forms of atrioventricular block, left bundle branch block, and right bundle branch block. Of interest was that 6 of the 12 patients had focal necrosis of the conducting fibers when atrioventricular block was present; however, another 6 patients with atrioventricular block had intact conduction fibers and only an adjacent infarct. In those patients with left bundle branch block, 2 had no
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Arrhythmias
20
evidence of necrosis of the conduction system, but an adjacent infarct. In those patients with right bundle branch block, 3 had an adjacent infarct, none had evidence of focal necrosis and in 1 no lesion was seen. Some conduction defects may be transient in patients with acute myocardial infarction and thus one might not anticipate a specific lesion or focus of necrosis in the conducting fibers. The mechnisms suggested by HACKEL et al. [4], for the origin of transient conduction defects include: (1) altered ionic environment; (2) sublethal ischemia; (3) infiltrated leukocytes, and (4) vagal reflexes. Since potassium leaks from the necrotic tissue, it may alter the function of conduction tissue, if the infarct is adjacent to conducting fibers. Evidence for this has been shown by UOELNOV [10] who excised necrotic muscle from a dog heart, placed it on a normal dog heart and showed arrhythmia induction. In sublethal ischemia, there can be an influx of sodium and efflux of potassium from the conducting fiber with loss of membrane resting potential. But the severity of this is not sufficient to induce tissue necrosis since arrhythmias frequently occur at the time when leukocytic infiltrate is maximal in the tissue and release of lysosomal enzymes may also have an effect on conducting tissue. The explanations offered for conduction fiber sparing in acute myocardial infarction include: (1) separate blood supply; (2) direct oxygen diffusion, and (3) metabolic differences. Although separate blood supply to the conduction system has been proposed, there is no evidence to support this. The blood supply to the conducting tissue is similar to that which is interrupted when acute myocardial infarction ensues. So, this is an unlikely explanation. Since the major parts of the conduction system lie close to the endocardial surface, direct oxygen diffusion may occur from the ventricular chambers and suffice to maintain viability of the conduction tissue. HACKEL et al. [4], have reported a case in which focal necrosis of the right bundle was localized to the site furthest away from the right ventricular chamber supporting such an explanation. In addition, conduction tissue has certain metabolic differences from normal myocardium. The conduction fibers have a higher glycogen content and their oxygen consumption is less; thus, under anaerobic conditions, their higher glycogen content may have enabled them to survive for a longer time. SCRIEBLER et al. [8] showed the oxygen consumption of conduction fibers in the myocardium to be 20% of values obtained from normal myocardial fibers. This relates to the difference in contractile activity of the other fibers. Thus, under hypoxic conditions, the oxygen demand of conduction tissue may still be met by the low flow levels present.
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BLOOR/RoESKE/O'RoURKE
Clinical Pathologic Correlates
21
Reperfusion
When the myocardium is reperfused after coronary occlusion, certain changes in the flow response may occur that affect infarct size. The ability of the coronary vascular bed to dilate and flow during reperfusion is partly dependent on the duration of the occlusion. BLOOR and WHITE [2] have shown that if occlusion is greater than 6 h, a significant decrease in the functional capacity of the coronary bed occurs on reperfusion, and may require 4-5 days before it recovers to the normal level. This influences the ensuing infarct size, namely the longer recovery time for coronary vascular capacity to return to control levels, the larger the infarct size. In addition, regional changes in flow distribution after coronary artery occlusion also occur. BISHOP et al. [1] showed a central core zone in large infarcts in which flow decreased at the onset of occlusion to about 10% of control level and, after 4 or 5 days, showed no change. The subendocardial zone, in particular, seems most vulnerable. Even though reperfusion is established early, most tissue in the endocardial zone becomes necrotic. Thus, any change in infarct size results from salvaging tissue in the marginal zone. Whether it is possible to salvage tissue from the endocardial region or central part of the infarct is not known.
The following correlations have been conducted in acute myocardial infarction patients. Figure 3 shows the relationship between old infarct and new infarct in this autopsied population group. Patients dying within 24 h or who died of non cardiac causes during the follow-up period have been excluded from this analysis. There is an inverse relationship between the extent of old infarct and the new infarct. This would be expected if patients died with equivalent hemodynamic embarrassment from infarct size and were not maintained by heroic measures while large new areas of infarction developed. It is interesting to note that the intercepts on the two axes are different. This suggests that the patients with prior myocardial infarcts died with total (old plus new) infarct sizes that were larger than patients who only had one infarct. Although a certain threshold of infarct size seems to be a major determinant of mortality in the disease, the latter feature suggests that some compensation may occur in the postmyocardial infarction patient who tends to have larger infarct size before death occurs.
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Clinical-Pathologic Correlations in Myocardial Infarction Patients
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BLOOR/RoESKE/O'RoURKE
20
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We studied the relationship between the extent of vessel involvement in the 4 major coronary arteries, namely the left main, left anterior descending, left circumflex, and right coronary arteries and the total infarct size as determined at autopsy. In 5 % of patients, none of the 4 major vessels had greater than 70 % occlusion. The possible etiologies for this include: (1) limitation of arteriography; (2) functional coronary constriction; (3) small vessel disease; (4) platelet aggregation; (5) abnormal hemoglobin, and (6) redistribution of coronary flow. Of these possible etiologies, functional coronary constriction, platelet aggregation, and redistribution of coronary flow may occur when the individual is subjected to extreme flow seem the most likely. Even when coronary atherosclerosis results in less than 70 % constriction of the vessel, significant redistribution of coronary stress, and thus render the endocardial region more vulnerable to ischemic injury. In general, involvement of I or 2 coronary vessels resulted in intermediate degrees of infarct size noted at autopsy while when 3 of the 4 major coronaries had greater than 70 % occlusion, infarct size at time of death averaged 23 %. Analysis of variance showed statistical significance (p < 0.05), indicating that the total infarct size is highly dependent on the extent of coronary atherosclerosis. Next, we determined the relation between infarct size and a history of a prior myocardial infarct. Although some patients without a history of
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Fig. 3. Relation between new and old infarcts (expressed as a percentage of heart weight) as determined at autopsy.
Clinical Pathologic Correlates
23
myocardial infarction had a significant amount of old infarct noted at autopsy, there was a considerable number of old infarcts present in those patients who had a positive history. It is also interesting to note that patients with previous myocardial infarction died with less new infarct than did those patients without a positive history. This supports the concept that there is a threshold level of infarct which can be tolerated before a patient dies of hemodynamic embarrassment. The fact that the total infarct size is greater in those patients having a history of prior myocardial infarction suggests that some degree of compensation occurred in those patients. VAN TAssEL and EDWARDS [9] report myocardial rupture to occur in approximately 5 % of autopsy patients with acute myocardial infarction. It is usually seen in older individuals and is most frequent within the first week of the onset of acute myocardial infarction. Interestingly, NAEIM et af. [6] report that hearts of individuals with acute myocardial infarction resulting in rupture weigh less than those of patients with acute myocardial infarction without rupture. This suggests that compensatory hypertrophy may be beneficial in reducing the incidence of rupture. In our study, 7 patients with left ventricular rupture had a new infarct size of 16 % while 30 patients without ventricular rupture had an infarct size of 8 % which was significantly different (p < 0.05). In 5 patients with septal rupture, there was a greater amount of new infarct compared to the group who did not have septal rupture. Finally, we determined the amount of old and new infarct in patients having left ventricular aneurysm at autopsy. In contrast to the 2 groups of patients with left ventricular rupture and septal rupture, patients with aneurysms had significantly more old infarct documented and had the highest group average of any selected group of patients with old myocardial infarct size. These patients also died with the smallest additional amount of new myocardial infarct. The amount of new infarct was significantly less than the new infarct size seen in remaining patients.
In this patient population representing all patients dying after myocardial infarction who had infarct size determined at autopsy, there was a lack of correlation between infarct size and a variety of clinical data including heart rates, systolic blood pressure or radiographic heart size at the time of admission. Furthermore, the MIRV class on admission (class I-IV) did not correlate significantly with the extent of infarct at the time of autopsy. In contrast to the lack of correlation from any clinical variables, we concluded
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Summary
BLOOR/RoESKE/O'RoURKE
24
that total (old plus new) infarct size at autopsy was indeed related to the extent of coronary atherosclerosis present at autopsy. Patients with a history of prior myocardial infarction or with left ventricular aneurysms died with a greater total (old plus new) infarct size. These data suggest that a larger total infarct is necessary to produce mortality in patients who have compensatory changes from an old infarct. The patients expiring with only a new infarct frequently have the complications of left ventricular or septal rupture. These patients died with infarct sizes which averaged 15 % of left ventricular mass. The use of autopsy infarct size provides an important tool for validation of many methods that are currently involved in reducing infarct size, determined in vivo. These data suggest that infarct size correlates most highly with the extent of coronary atherosclerosis and not with the clinical variables associated with poor prognosis in an unselected population of postmyocardial infarction patients.
References
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BISHOP, S. P.; WHITE, F. C., and BLOOR, C. M.: Regional myocardial blood flow during acute myocardial infarction in the conscious dog. Circulation Res. 38: 429-438 (1976). BLOOR, C. M. and WHITE, F. C.: Coronary artery reperfusion: effects of occlusion duration on reactive hyperemia responses. Basic Res. Cardiol. 70: 148-158 (1975). HACKEL, D. B. and RATLIFF, M. B.: A technique to estimate the quantity of infarcted myocardium post-mortem. Am. 1. clin. Path. 61: 242-246 (1974). HACKEL, D. B.; WAGNER, 0.; RATLIFF, N. B.; CIES, A., and ESTES, E. H., jr.: Anatomic studies of the cardiac conducting system in acute myocardial infarction. Am. Heart 1. 83: 77-81 (1972). HALES, M. R. and CARRINGTON, C. B.: A pigmented gelatin mass for vascular injection. Yale 1. BioI. Med. 43: 257-270 (1971). NAEIM, F.; MAZA, L. M. DE LA, and ROBBINS, S. L.: Cardiac rupture during myocardial infarction. A review of 44 cases. Circulation 45: 1231-1239 (1972). ROBERTS, W. C. and BUJA, L. M.: The frequency and significance of coronary arterial thrombi and other observations in fatal acute myocardial infarction: a study of 107 necropsy patients. Am. J. Med. 52: 425-443 (1972). SCHLIEBLER, T. H.; STARK, M. und CAESAR, R.: Die Stoffwechselsituation des Reizleitungssystems. Klin. Wschr. 34: 181-183 (1956). TASSEL, R. A. VAN and EDWARDS, J. E.: Rupture of heart complicating myocardial infarction: analysis of 40 cases including nine examples of left ventricular false aneurysm. Chest 61: 104-116 (1972). UDELNOV, M. 0.: The role of necrosis in the origin of electrocardiographic alterations characteristic of myocardial infarction. Circulation 24: 110--122 (1961).
Dr. C. M. BLOOR, Departments of Pathology and Medicine, UCSD School of Medicine, La Jolla, CA 92093 (USA)
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