Download S Koyanagi, CL Eastham, DG Harrison and ML Marcus

Increased size of myocardial infarction in dogs with chronic hypertension and left
ventricular hypertrophy.
S Koyanagi, C L Eastham, D G Harrison and M L Marcus
Circ Res. 1982;50:55-62
doi: 10.1161/01.RES.50.1.55
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55
Increased Size of Myocardial Infarction in
Dogs with Chronic Hypertension and Left
Ventricular Hypertrophy
SAMON KOYANAGI, CHARLES L. EASTHAM, DAVID G. HARRISON, AND
MELVIN L. MARCUS
SUMMARY Impaired coronary reserve in animals and patients with left ventricular hypertrophy
(LVH) might be expected to augment infarct size following coronary occlusion (CO). To test this
hypothesis, the circumflex coronary artery was acutely occluded in 30 control dogs and in 28 renal
hypertensive (HT)-LVH dogs during the conscious state. Hemodynamics and regional myocardial flow
(microspheres) were measured. After 48 hours of CO, we assessed infarct size pathologically and area
at risk by postmortem coronary angiography. Mean arterial pressure (130 ± 5 mm Hg) and LV:body
weight ratio (6.1 ± 0.1 g/kg) in HT-LVH dogs were about 35% greater than in control dogs (P < 0.05).
During the 48 hours following CO, mortality rate was markedly increased in HT-LVH (54%) compared
to control (17%) (P< 0.01). We performed a linear regression analysis of the relationship between area
at risk (AR; % of LV mass) and infarct size (IS; % of LV mass); control, IS = 1.20AR - 25.6 (r = 0.96);
HT-LVH, IS = 1.19AR - 16.3* (r = 0.95) (*P< 0.05 vs. control). Although the slopes of these relationships
were similar, the intercepts were different. Consequently, the minimal AR associated with infarction
was 35% smaller in HT-LVH (15 ± 2% of LV mass) than in control (22 ± 1%), and over the entire range
of AR, the IS was increased in HT-LVH. The distance between the lateral extent of infarct size and area
at risk in different layers of LV was measured. The increase in infarct size in the HT-LVH group
reflected primarily an increase in midwall layer infarction. Increase in collateral flow to the risk area
was attenuated in HT-LVH. In conclusion, infarct size relative to the area at risk is increased significantly in HT-LVH. This interaction between LVH and myocardial ischemia may significantly influence
the outcome of myocardial infarction in patients with hypertension and LVH. Circ Res 50: 55-62, 1982
PATIENTS with systemic arterial hypertension are
particularly susceptible to coronary artery disease
(Robertson and Strong, 1968). Furthermore, once
myocardial infarction occurs, it is much more likely
to be fatal in patients with hypertension and left
ventricular hypertrophy (LVH) than in normotensive patients (Kannel et al., 1969; Kannel, 1974;
Kannel et al., 1975; Rabkin et al., 1977). The high
morbidity and mortality from myocardial infarction
have been attributed generally to accelerated occlusive atherosclerotic coronary lesions secondary to
hypertension (Perper et al., 1973; Pick et al., 1974;
Hollander et al., 1977). However, other factors could
also contribute to the deleterious effects of coronary
occlusion in hypertensive patients. Prolonged hypertension induces LVH. Ventricular hypertrophy
increases the diameter of myocardial cells without
a proportional proliferation of capillary vessels (ToFrom the Cardiovascular Center and the Department of Internal
Medicine, University of Iowa and Veterans Administration Hospitals,
Iowa City, Iowa.
These studies have been supported by Program Project Grant
HL14388, National Institutes of Health Research Grant HL20827, and a
research grant from the Veterans Administration. Dr. Marcus is the
recipient of Research Career Development Award HL00328 from the
National Heart, Lung, and Blood Institute.
Address for reprints: Melvin L. Marcus, M.D., Department of Internal
Medicine, University of Iowa Hospitals, Iowa City, Iowa 52242.
Editorial decisions with regard to this manuscript were made by
Robert M. Berne, Consulting Editor.
Received June 17, 1981; accepted for publication September 1, 1981.
manek, 1979; Murray et al., 1979; Breisch et al.,
1980). Also, many recent studies suggest that coronary vasodilator reserve is compromised in LVH
both in humans and animals (Mueller et al., 1978;
O'Keefe et al., 1978; Rembert et al, 1978; Marcus
e t a l , 1980).
These fundamental abnormalities in the coronary circulation may potentiate the adverse effects
of ischemic injury in LVH. Therefore, we hypothesized that the extent of myocardial infarction following sudden coronary occlusion may be greater
in pressure-induced LVH. The experiments described in this manuscript support this hypothesis.
Methods
Preparation of the Dogs
Systemic hypertension was induced in 28 adult
mongrel dogs (weight: 14-27 kg). The method of
producing hypertension has been described previously in detail (Mueller et al, 1978) and will be
summarized briefly.
Under sodium pentobarbital anesthesia (30 mg/
kg, iv), a bilateral flank incision was performed
under sterile conditions. An externally adjustable
clamp, described by Ferrario et al. (1971), was implanted around a renal artery and tightened until a
thrill could be felt at the distal renal artery. Then
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56
CIRCULATION RESEARCH
the kidney on the contralateral side was removed.
A second surgical procedure was performed 6-8
weeks after the renal surgery. The dogs were anesthetized with sodium pentobarbital (30 mg/kg, iv),
ventilated with a respirator, and a left thoracotomy
was performed through the 4th intercostal space.
Catheters were placed in the ascending aorta
through the left internal mammary artery and in
the left atrium through its appendage. A 1-0 silk
snare was placed around the circumflex coronary
artery distal to the first or second marginal branch
(1-3 cm from the origin of the circumflex artery) in
19 dogs. In the other nine dogs, snare was placed
distal to the second marginal branch (3-5 cm from
the origin of the circumflex artery). The snare and
the catheters were tunneled subcutaneously and
attached to skin buttons at the back. The catheters
were filled with heparin (1000 U/ml) and flushed
every other day.
Thirty adult mongrel dogs (weight: 17-29 kg)
were used as controls. These dogs also underwent
thoracotomy for placement of catheters and a coronary arterial snare. The snare was placed around
the circumflex artery distal to the first marginal
branch (n — 20) or the second marginal branch (n
= 10).
Experimental Protocol
Studies were performed 7-12 days after the thoracotomy when all dogs appeared healthy and were
free from severe infection, anemia (hematocrit was
38-45%) or chronic renal failure (serum creatinine
was <1.8 mg/ml). About 20 minutes before the
experiment, morphine sulfate (2-5 mg) was given
intramuscularly. The arterial and left atrial catheters were connected to Statham P23dB strain
gauges placed at midchest level. Aortic and left
atrial pressures and the lead II electrocardiogram
were recorded continuously.
When the dogs were lying quietly and hemodynamics were stable, myocardial blood flow was measured with microspheres. Lidocaine (1.5 mg/kg, iv)
was then administered, and the circumflex coronary
artery was acutely and totally occluded with the
exteriorized snare. Some dogs became restless immediately after the occlusion, but that was usually
transient. Ventricular fibrillation occurred in three
control dogs (10%) and eight hypertensive dogs
(29%) within 2 hours. Although cardiopulmonary
resuscitation was performed, none of these dogs
recovered. In surviving dogs, measurements of hemodynamics and myocardial blood flow were obtained 5 minutes, 2 hours, and 48 hours after coronary occlusion. The dogs then were anesthetized
with sodium pentobarbital and killed with potassium chloride.
Measurement of Regional Myocardial
Perfusion
Regional myocardial perfusion was measured, using carbonized radioactive microspheres 7-10 jiim in
VOL. 50, No. 1, JANUARY 1982
diameter labeled with 46Sc, 85Sr, 95Nb, 113Sn or 125I.
For each flow measurement, 20-juCi microspheres
(11.6 ± 0.7 X 106) were injected through the left
atrial catheter, which was subsequently flushed
with 10 ml of saline over 10 seconds. Prior to the
injection, the vial containing the microspheres suspended in 10% dextran and 0.05% of Tween-80 was
mechanically agitated for at least 5 minutes. A
reference arterial blood sample was withdrawn from
the catheter in the aortic arch at a constant rate of
2.06 ml/min with a Harvard pump, starting 20
seconds before microsphere injection and continuing until 2 minutes after injection. During measurements of blood flow with microspheres, a continuous electrocardiogram showed no arrhythmias or
significant change in heart rate. Left atrial pressure
and arterial pressure did not change significantly
before or after microsphere injection.
For analysis of perfusion, myocardial samples
were obtained from the following regions: normally
perfused region (non-risk region perfused by left
anterior descending coronary artery), border region
5 mm lateral to the area at risk, normal appearing
region within the area at risk, and infarct region.
Each region was subdivided into subepicardial, midwall, and subendocardial layers of about equal
thickness. In the infarct area, the posterior papillary
muscle was separated from other endocardial segments. A transition zone about 2 mm wide between
the normal-appearing risk region and infarct area
was excluded from perfusion analysis to avoid crosscontamination. Myocardial segments were weighed,
placed in plastic scintillation tubes, and counted for
5 minutes in a 3-inch well counter. Myocardial
blood flow in each sample was calculated by the
formula:
MBF = (Cm x 100 x RBF)/Cr
where MBF = myocardial blood flow (ml/min X
100 g), Cm = counts/g of myocardium, RBF =
reference blood flow (the rate of withdrawal from
the reference artery), and Cr = total counts in the
reference blood.
Measurement of Infarct Size and Area at
Risk
After the heart was excised, cannulas (o.d. = 2-3
mm) were secured in the left main and right coronary arteries. When the left anterior descending
coronary and the left circumflex coronary artery
had separate orifices from the aorta, each artery
was cannulated at its origin. Cannulas were flushed
with saline to remove blood from coronary vessels.
A barium-gelatin mixture then was perfused simultaneously into the coronary vessels at a perfusion
pressure of 50 mm Hg, and sites of leakage were
stopped by ligation. Then, the perfusion pressure
was increased to 20 mm Hg higher than the mean
aortic pressure in situ (about 120 mm Hg in control
dogs and 150 mm Hg in hypertensive dogs) and
maintained for 5 minutes. The total volume of
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INCREASED INFARCT SIZE IN HYPERTROPHIED HEART/Koyanagi et al.
injectate was 5-7 ml. After the hearts were fixed in
10% formaldehyde overnight, stereoscopic radiographs of the whole heart were taken. The atria
and the right ventricle were removed, and the left
ventricle was sectioned into seven transmural slices
of approximately equal thickness (0.8-1.1 cm) parallel to the atrioventricular groove. Stereoscopic
radiographs of the ventricular slices were then
taken without magnification. Microscopic examination showed that the injectate filled the coronary
vessels to the arteriolar level in all hearts. The
barium-gelatin mass filled the arterial bed distal to
the occlusion in dogs that survived more than 24
hours after occlusion. However, in the dogs that
died immediately after coronary occlusion, the distal bed was not filled with injectate because of
inadequate collaterals. The perfusion area of the
occluded artery, i.e., the area at risk, was determined by carefully following the course of occluded
and non-occluded vessels by means of stereoscopic
views of the transverse slices and whole left ventricular arteriograms.
Infarct area was determined by gross pathological examination. After 24 hours of coronary occlusion, the infarcted myocardium was clearly delineated from the surrounding normal muscle. Then,
the tracings of the area at risk and the infarct area
of the top of each slice were superimposed, and the
normal area, infarct area, and area at risk of all
slices were measured using computerized planimetry. The infarct and risk area for subepicardium,
midwall, subendocardium, and papillary muscle
were measured independently.
Thereafter, the ventricular slices were trimmed
of the right ventricle, connective tissue, and epicardial large vessels, and weighed. The mass of each
risk and infarct region was calculated by multiplying the average area of the top and the bottom of a
slice expressed as a percentage of total area times
the weight of the slice. For each heart, these various
regions were summated. Area at risk and infarct
area were determined by two observers, independently. The interobserver difference was minimal:
0.3% of left ventricular weight for mass of risk region
and 0.2% for infarct mass.
Histology
Myocardial segments selected from each dog
were fixed in a 10% buffered formalin solution for
at least 2 weeks. These segments were prepared for
histological sections using hematoxylin and eosin
stain and examined by two observers. Histological
criteria for myocardial infarction include pyknosis,
karyorrhexis, karyolysis, fiber fragmentation, polymorphonuclear cell infiltration, loss of cross-striations of myocardial fibers, and deep eosinophilic
appearance of fibers (Maroko et al., 1971). A tissue
area was not classified as infarcted unless at least
two of the above criteria were filled. The estimated
extent of infarction was expressed as a percentage
of total area in each specimen.
57
Data Analysis
The data are presented as mean values ± SE, and
the level of statistical significance was P < 0.05.
Hemodynamic and myocardial bloodflowdata were
analyzed by analysis of covariance with multiple
comparisons performed using Duncan's multiple
range test. Comparison of left ventricular weight
between groups were made by unpaired <-test. Chisquare test was used to analyze the difference in
mortality rate and lateral border width between
groups. Regression lines were fitted to the grouped
data using the least-squares method. The slopes
and the intercepts of the regression lines of the
relationships between infarct size and area at risk
were compared using an unpaired t-test.
Results
Anatomical Characteristics
Left ventricular weight was 101 ± 4 g in control
dogs, and 126 ± 4 g in hypertensive dogs (P < 0.05).
The left ventricular weight-to-body weight ratio
was 4.5 ±0.1 g/kg in controls and 6.1 ± 0.1 g/kg in
hypertensives (P < 0.01). Thus, left ventricular
mass was increased by about 35% in hypertensive
dogs.
Mortality Rate
During the 48 hours after coronary occlusion, 5
of 30 control dogs (17%) died, whereas 15 of 28 dogs
(54%) with hypertension and left ventricular hypertrophy (HT-LVH) died (P < 0.01). However, the
risk area was similar in the control group (31 ± 2%
of left ventricular mass) and in the HT-LVH group
(30 ± 2%). The risk area in dogs that died prematurely (30 ± 2%) was not significantly different from
that in survival dogs (31 ± 2%). Furthermore, increases in left ventricular mass and arterial pressure
were almost identical between the dogs that died
prematurely and the survival dogs in HT-LVH
group. Among these animals, 4 control and 12 HTLVH died too soon (less than 24 hours) to allow
assessment of infarct size. Accordingly, these 16
dogs were excluded from further analysis.
Hemodynamic Changes (Table 1)
During the control state, aortic pressure was
about 35% higher (P < 0.05) in the HT-LVH group.
Heart rate and left atrial pressure were similar in
the control and HT-LVH groups. After coronary
occlusion, heart rate and left atrial pressure increased to a similar extent in both groups. Aortic
pressure decreased in the HT-LVH group, but aortic pressure remained higher than that of the control group during the 48 hours following occlusion.
Relationship between the Size of Myocardial
Infarct and the Area at Risk
Overall, the infarct:risk ratio was higher in the
HT-LVH group than in the control group (P < 0.05,
Table 2). The relationship of the infarct size and
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58
CIRCULATION RESEARCH
VOL. 50, No. 1, JANUARY 1982
1 Hemodynamic Effects of Sudden Coronary Occlusion in Control Dogs and
Hypertensive Dogs with Left Ventricular Hypertrophy
TABLE
Post-occlusion
Before
occlusion
Heart rate (beats/min)
Control
HT-LVH
5 min
48 hr
2hr
93 ±4
94 ± 5
109 ± 5 t
123 ± 7t
110 ± 5t
106 ± 5 t
112 ±5t
111 ± 6J
Systolic arterial pressure (mm Hg)
Control
HT-LVH
118 ± 3
166 ± 6*
111 ± 2f
144 ± 5't
116 ± 3
137 ± 5't
109 ± 2t
133 ± 5*t
Mean arterial pressure (mm Hg)
Control
HT-LVH
94 + 2
130 ± 5'
93 ± 1
123 ± 4'
97 ± 2
115 ± 5*t
89±2t
110±5*t
Diastolic arterial pressure (mm Hg)
Control
HT-LVH
81 ±2
112 ± 4 '
83 ± 1
110 ± 3'
86 ± 3
103 ± 5*t
11 ±2
95 ± 4*t
6± It
7± 1
6± It
7±lt
Left atrial pressure (mm Hg)
Control
HT-LVH
4±1
6± 1
7±lt
7±lt
Values are mean ± SEM. HT-LVH = hypertension with left ventricular hypertrophy.
* P < 0.05 compared to control group.
t P < 0.05 compared to preocclusion value.
the area at risk was plotted for individual dogs (Fig.
1). The linear regression line was estimated using
only points with infarction in both groups (n = 21
for controls, n = 15 for HT-LVHs). Although the
slope of the relationship was similar in the control
and HT-LVH groups, the intercept for zero-infarct
was shifted from 22.5% ± 1.1 in controls to 15.5%
± 1.7 (P < 0.05) in HT-LVH dogs. Consequently,
overall infarct size in the HT-LVH group was
greater than that in the control group over the
entire range of risk areas that we examined.
We also determined the infarct-risk relationships
in various transmural layers (Koyanagi et al., in
press). In the subendocardial and midwall layers,
the zero-infarct intercepts of the infarct-risk relationship were significantly decreased in the HTLVH group (Table 3). Increased size of infarction
in the HT-LVH group occurred to a small extent in
the subendocardium and to a moderate degree in
the midwall layer, but not in the epicardial layer.
Lateral Border Zone
The distance between the lateral margin of the
area at risk and the lateral extent of infarct area
was narrowest at endocardium and widest at epicardium in both the control and HT-LVH groups.
Frequency histograms of the lateral border width
(Fig. 2) indicated that, in the endocardial and midMass of Infarct Area/
LV Mass (%)
O HT-LVH
• Control
50
40 -
TABLE 2 Comparison of Masses of Infarct and Risk
Region in Control Group and Hypertensive LVH
Group
Number
Control group
HT-LVH group
26
16
32.5 ±3.4
30.8 ±2.5
36.9 ±3.6
30.1 ±2.9
Mass of infarct region
gram
% of LV mass
14.2 ±3.2
12.9 ±2.7
23.7 ±4.6
19.4 ±3.6
31.3 ±5.6
53.9 ±8.7*
Mass of infarct/mass of
risk area X 100
Values are mean ± SEM. HT-LVH = hypertension with left ventricular
hypertrophy.
' P < 0.05 compared to control group.
/
}/
30 20 -
'x
•• •
0
r = 0 96
y = 1 20x - 25 6
'
10 _
n
Mass of risk region
gram
% of LV mass
r = 0.95
y = 1.19x • 163
10
i
I
20
30
40
Mass of Risk Area/LV Mass (°-o)
I
50
60
FIGURE 1 Relationship between the masses of infarct
and risk region normalized by LV mass in the control
group (closed circles) and in the hypertensive-LVH
group (open circles). There was a close relationship for
each group. However, significant alteration in relationship was observed between groups; the intercept of xaxis (area at risk for which infarct does not occur) was
22.5% ± 1.1 of LV mass for control group and 15.5% ±
1.7 for hypertensive-LVH group (P < 0.05).
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INCREASED INFARCT SIZE IN HYPERTROPHIED HEART/Koyanagi et al.
TABLE
59
3 Relationship between Infarct Size and Area at Risk
Control group
Regression equation
y=
y=
y=
y=
Transmural
Endocardium
Midwall
Epicardium
1.20x
1.36x
1.21x
0.92x
-
25.6
6.3
8.1
7.8
r
Hypertensive-LVH group
x-intercept {%) Regression equation
0.96
0.91
0.97
0.92
22.5
5.5
7.1
9.2
± 1.1
± 0.3
± 0.6
± 0.4
y
y
y
y
= 1.19x
= 1.28x
= 1.15x
= 0.72x
-
16.3
3.9
4.2
2.7
x-inlercept
0.95
0.95
0.95
0.59
15.5 ± 1.7*
3.7 ± 0.5*
4.3 ± 0.7'
9.2 ± 1.8
Values are mean ± SEM. x = mass of risk region/left ventricular mass (%); y = mass of infarct region/left
ventricular mass (%).
* P < 0.05 compared to control group.
wall layers, the lateral border width was smaller in
the HT-LVH group than in the control group. The
endocardial lateral border was less than 1 mm wide
in 45% of the ventricular slices for the control group,
and in 64% for the HT-LVH group (P < 0.01). The
midwall lateral border was less than 3 mm wide in
35% of the ventricular slices for the control, and in
70% for the HT-LVH group (P < 0.01).
Regional Myocardial Blood Flow (Table 4)
Prior to coronary occlusion, myocardial blood
flow was similar in the control and HT-LVH groups.
The endocardial-to-epicardial flow ratio was also
similar: 1.14 ± 0.03 for control and 1.19 ± 0.01 for
the HT-LVH group. Prior to occlusion, the ratio of
perfusion in the infarct area to perfusion in the
normal area was not significantly different from
unity: 0.99 ± 0.02 in the control group and 0.95 ±
0.02 in the HT-LVH group. This indicates that
microsphere loss from the infarct region was negligible.
Five minutes after coronary occlusion, myocardial blood flow decreased by 87% (range: 65-95%)
in the infarct area and by about 36% (range: 0-72%)
in the normal-appearing risk area in the control
group. These values were almost identical in the
HT-LVH group. By 2 hours post-occlusion, the
blood flow to the normal appearing risk area in-
creased by about 20% in the control group (P <
0.05). In contrast, there was no change in blood flow
to the normal appearing risk area in the HT-LVH
group.
During the following 46 hours, the blood flow to
the normal-appearing risk zone returned to preocclusion level in both groups. In the infarct zone,
with the exception of the epicardium, blood flow
remained severely depressed, especially in the HTLVH group. In the normally perfused area, the
border area, and the normal-appearing risk area,
myocardial perfusion for the HT-LVH group tended
to be higher than the control group. However, these
differences were not statistically significant.
The Histological Extent of Myocardial
Necrosis
The myocardial samples from the normally perfused and border areas were completely free of
necrosis or significant fibrosis, on histological examination. In the normal-appearing risk area, 13 ±
3% and 12 ± 2% of the tissue demonstrated histological evidence of infarction in the control group
and HT-LVH group, respectively. Segments that
were infarcted by gross insepction contained 7 ± 3%
and 3 ± 2% of the normal tissue in the control group
and HT-LVH group, respectively.
50
Endo
Mid
Epi
Control
Group
Percent
Slices
Examined
rrtrfflfl JTWl
"mlUi
n.
50
HT-LVH
Group
0
10
20 0
10
20 0
10
20
30 40
Lateral Border Width (mm)
FIGURE 2 Frequency histogram of the distance between lateral margins of risk area and infarct area for various
transmural layers in control and hypertensive (HT)-LVH groups. Lateral border was narrower in the inner layer of
the left ventricle. In the subendocardial and the midwall layers, the lateral border was narrower in the hypertensiveL VH group than in the control group.
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CIRCULATION RESEARCH
60
VOL. 50, No. 1, JANUARY 1982
TABLE 4 Effects of Sudden Coronary Occlusion on the Regional Myocardial Blood Flow
Control group
Hypertensive-LVH group
Postocclusion
No.
Before
occlusion
5 min
Normally perfused area
17
Transmural
17
Endocardium
17
Epicardium
100 ± 8
103 ± 8
93 ± 7
98 ± 10
108+ 12
91 ± 9
Border area
Transmural
Endocardium
Epicardium
104 ± 8
110 + 7
95 + 8
106 ± 12
112 ± 12
99 ± 12
Normal-appearing risk area
17
Transmural
17
Endocardium
17
Epicardium
101 ± 7
103 ± 7
96 ± 7
65 ± 7*
58 ±9*
69 + 5*
80 ± 7'f
76 ±8*
86 ± 7't
Infarct area
Transmural
Endocardium
Epicardium
PPM
107 ± 11
108 ± 13
88 ± 10
137 ± 15
14 ± 2*
10 ± 2*
19 ± 3*
9 ± 3*
26 ±6*
19 ±5*
32 ±8*
18 ±8*
17
17
17
14
13
10
10
Postocclusion
48 hr
No.
Before
occlusion
104 ±9
108 ±9
97 ± 8
108 ± 12
110 ± 12
100 ± 11
13
13
13
111 ± 8
118 ± 8
100 ± 9
128 ± 11
131 + 11
120 ± 11
104 ± 9
108 ± 9
95 ± 9
112 ± 13
117 ± 13
104 + 13
110 ± 9
118 ±9
100 ±9
113 ± 11
121 ± 12
105 ± 11
13
13
13
117 ± 8
125 + 8
106 ± 8
127 ± 11
138 ± 14
114 ± 10
109 ± 9
122 ± 10
97 ± 8
118 ± 12
134 ± 14
107 ± 12
107 ± 9 *
109 ±11*
106 ± 10$
13
13
13
109 ± 8
119 ± 9
98 ± 8
73 + 8*
83 ± 10*
67 ± 7*
75 ± 7*
92 ±8*
65 ±6*
113 ± 12*
120 ±
103 ± 12*
12
11
8
10
108 ± 10
108 ± 10
92 ± 10
125 ± 13
14 + 2*
13 + 2*
23 ±4*
4 ± 1*
20 ±4*
13 ± 3*
25 ±6*
11 ±4*
2hr
44
37
60
32
±7*f
± 10*t
± 12*j*
+ 9*
5 min
2hr
48 hr
44 ± 9*t*
25 ± 9*
66 ± 9*f*
15 ± 10*
Values are mean ± SEM (ml/min per 100 g). PPM-posterior papillary muscle.
' P < 0.05 compared to value before occlusion.
t P < 0.05 compared to value 5 minutes postocclusion.
X P < 0.05 compared to value 2 hours postocclusion.
Discussion
We have demonstrated that, following acute coronary occlusion, myocardial infarct size is increased
substantially in pressure overload LVH. The increase in infarct size was most prominent in the
midwall layer. This discussion will focus on methodological considerations and speculation about
mechanisms that may increase infarct size in pressure-overload LVH.
Methodological Considerations
There are several advantages of the experimental
design and the methods that we employed. First,
because the most common cause of LVH in patients
is hypertension, we chose as our experimental
model dogs with chronic hypertension and LVH.
Second, we produced myocardial infarction when
the dogs were conscious to avoid the adverse effects
of anesthesia and surgical trauma. Third, for the
purpose of assessing infarct size, we determined the
relationship between infarct size and the perfusion
field of occluded artery, or area at risk, in control
and hypertensive LVH dogs. This is of critical importance because the perfusion area of the coronary
artery at the same anatomical site is highly variable
between dogs (Lowe et al., 1978; Jugdutt et al.,
1979a), and the perfusion field at a given coronary
vessel may be altered with cardiac enlargement. We
have demonstrated that the relationship between
infarct and risk area varies in different transmural
layers of the left ventricle (Koyanagi et al., in press).
By using this approach, we could define the specific
layers of the left ventricular wall in which hyper-
tension and LVH augmented infarct size. We estimated the area at risk using postmortem stereoscopic coronary arteriography. The advantage of
this method is that the three-dimensional "anatomical" risk zone can be obtained in the heart several
days after coronary occlusion (Schaper et al., 1979;
Jugdutt et al., 1979a). The infarct area was determined by gross inspection, because the infarct zone
was clearly delineated from surrounding normal
tissue after 24 hours of coronary occlusion. Reproducibility of the estimation of risk area and infarct
area was excellent: the interobserver or intraobserver difference was almost negligible (<1% of LV
mass). Thus, the methods we used to estimate
infarct size and the area at risk in our study are
reasonably precise.
There are several limitations of our study. First,
several studies have shown that microspheres injected prior to coronary occlusion are lost from
necrotic tissue during the first several days of infarction (Capurro et al., 1979; Jugdutt et al., 1979b;
Reimer and Jennings, 1979). However, Murdock
and Cobb (1980) recently have indicated that the
loss of microspheres does not significantly affect
the interpretation of serial measurement of collateral flow. Furthermore, the microsphere loss can be
minimized by using large number of microspheres
(6-20 X 106) (Koyanagi et al., in press; White et al.,
1978). In this study, 2 days after coronary occlusion,
the ratio of preocclusion measurement in the normal and infarct area was almost unity. Thus, microsphere loss from infarcted tissue was probably negligible.
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INCREASED INFARCT SIZE IN HYPERTROPHIED HEART/Koyanagi et al.
Second, the method used to determine the infarct
area and the normal-appearing risk area is not
perfect. Histological examination indicated that
about 12.5% of tissue was necrotic in myocardial
segments from the normal-appearing risk area.
Also, about 5% of tissue was not necrotic in myocardial samples from the infarct area. Some contamination seems to be technically unavoidable
because the border of infarct and normal tissue is
highly irregular (Factor et al., 1978; Jugdutt et al.,
1981). Thus, although some contamination was
present in our samples, fortunately the degree of
contamination was similar in the control and HTLVH groups.
Third, because over one-half of the hypertensive
dogs died prematurely, the survivors may or may
not be representative of the entire group. However,
the area at risk was almost identical between survivors and non-survivors. Furthermore, in survivors
and non-survivors, left ventricular mass and arterial
pressure were similarly increased. Thus, it is unlikely that increased mortality in HT-LVH group
biased the direction of our conclusion.
Potential Mechanisms of Increased Infarct
Size in Pressure-Overload Hypertrophied
Ventricles
Epidemiological studies have demonstrated that
mortality and morbidity from myocardial infarction
is increased in patients with arterial hypertension
(Kannel, 1974; Kannel et al., 1975; Rabkin et al.,
1977). The usual explanation for this is that hypertension augments the severity of coronary atherosclerosis and consequently the complications of coronary occlusive disease are exaggerated. We have
demonstrated that infarct size is larger in pressureinduced hypertrophied heart than in the normal
heart when the perfusion field of the occluded artery, or area at risk, is comparable. Thus, factors
other than the extent of coronary atherosclerosis
must play an important role in augmenting infarct
size in the presence of hypertension and LVH.
There are several mechanisms which should be
considered.
First, there is considerable evidence that cardiac
hypertrophy is associated with fundamental abnormalities in the coronary circulation. When cardiac
hypertrophy is produced in adult animals, capillary
proliferation does not keep pace with the hypertrophic process of myocardial cells (Rakusan et al.,
1969; Murray et al., 1979; Breisch et al., 1980).
Consequently, capillary density is decreased and
the diffusion distance from capillary to the center
of the myocardial cell is increased (Henquell et al.,
1977). In the presence of a marked decrease in flow,
this increase in diffusion distance may augment the
size of myocardial infarction. Furthermore, recent
studies have shown that coronary reserve is compromised in hypertrophied ventricles (Mueller et
al, 1978; O'Keefe et al., 1978; Rembert et al., 1978;
61
Marcus et al., 1980). These studies strongly suggest
that the anatomical and physiological abnormalities
in coronary circulation potentiate the adverse effect
of coronary occlusion in hypertrophied heart. It is
interesting to note that, in hypertrophied hearts,
impairment in the coronary circulation is greatest
at the subendocardial muscle (Mueller et al, 1978;
O'Keefe et al, 1978; Rembert et al, 1978). In this
study, the increase in infarct size in the dogs with
hypertension and LVH was due primarily to an
increase in the extent of infarct in the endocardial
and midwall layers of the left ventricle.
Second, differences in development of collateral
flow in normal and hypertrophied hearts may be
important. In our study, the decrease in blood flow
to the normal appearing risk area and the infarct
area immediately after coronary occlusion was similar in the control and hypertensive LVH groups.
Thus, the degree of reduction in myocardial flow
immediately after coronary occlusion could not explain the increased infarct size in the HT-LVH
group. However, the increase in collateral flow to
these ischemic areas was attenuated in hypertrophied hearts (Table 4). Although this trend did not
reach statistical significance, it could augment the
infarct size in LVH.
Third, oxygen consumption of the myocardium
or wall stress could have been augmented in hypertensive animals, which potentially increases ischemic injury. If so, infarct size may be less extensive when blood pressure is normalized after the
development of LVH.
Fourth, the renin-angiotensin system might have
affected the infarct size in the hypertensive dogs.
However, we think that the renin-angiotensin system had little effect in our experimental model,
because in chronic Goldblatt hypertensive animals
plasma renin activity is normal and [Sar1, Ala8]
angiotensin II, angiotensin II antagonist, does not
decrease blood pressure (Bianchi et al, 1970; Ferrario, 1974; Freeman et al, 1977; Stephen et al,
1979; Bing et al, 1981). However, neurohumoral
abnormalities associated with hypertension and
LVH other than the renin-angiotensin system could
contribute to the increase in size of myocardial
infarction.
Fortunately, since renal function appeared to be
within normal limits in the hypertensive dogs, it is
not likely that renal failure affected our study.
In conclusion, we have demonstrated that myocardial infarct size relative to the area at risk is
significantly increased in hypertensive dogs with
LVH. This increase in infarct size was shown in the
endocardial and midwall layers. This interaction
between LVH and myocardial ischemia may have
significant influence on the outcome of myocardial
infarction in patients with hypertension and LVH.
Acknowledgments
We express our appreciation to Alan Rakoff, Robert WLscow,
Darlene Harbuziuk, and Dawyn Sawyer for technical assistance
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CIRCULATION RESEARCH
62
and to Judy Bean for statistical analysis. We also thank Paula
Jennings for preparing the manuscript.
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