Download Print - Circulation

DECEMBER 1951
NO. 6
VOLl. IV
Circu latlion
The Journal of the American J fert Association
Anastomoses in the
Human Heart, with Particular Reference
to Anemia and Relative Cardiac Anoxia
Interarterial
Coronary
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By PAUL M. ZOLL, M.D., STANFORD WESSLER, M.D., AND MONROE J. SCHLESINGER, M.D.
In an unselected series of 1050 human hearts the coronaryv arteries were uniformly injected at
necropsy with a standardized radiopaque mass. Interarterial coronary anastomoses were clearly
demonstrated by this method and were studied faith respect to their incidence and pathogenesis.
Anastomoses were significantly increased in hearts with coronary artery occlusion or marked narpulmonale, in cardiac hypertrophy and valvular lesions, and also in normal hearts
rowing in
from patients with anemia. Relative cardiac anoxia is present in all these conditions; it appears to
be a common underlying stimulus for the development of interarterial coronary anastomoses.
cor
as bypasses or detours whereby blood reaches
vessels distal to occlusions. These observations
have been confirmed in the experimental animal.3 Other collateral channels, such as extracardiac anastomoses4-31 and communications of
the thebesian type4-6 9, 18, 21, 29 32-76 between
the cavities of the heart and coronary arteries,
capillaries or veins, have not appeared to be
significant in the maintenance of adequate coronary blood florw.
Any regimen that would produce interarterial
anastomoses so that the coronary arteries were
no longer functionally end-arteries would mitigate the clinical manifestations of coronary
artery disease. Knowledge of the factors influencing the development of interarterial coronary anastomoses, therefore, would be of great
practical value.
This paper presents the results of a study
of coronary interarterial anastomoses in a series
of 1271 human hearts examined by a uniform
technic of injection and dissection. This unique
body of data has provided a better understanding of the role of interarterial corollary anastomoses in normal and diseased states: insight
into the basic mechanism of their production
HE CLINICAL effects of coronary
arteriosclerosis, in the form of angina
pectoris, myocardial infarction and congestive failure, constitute a large portion of the
serious cardiac disabilities that the physician
constantly faces. Studies of atherosclerosis may,
at some future date, lead to the prevention of
T
these lesions. In the meantime, it has become
clear that narrowing or even occlusion of the
coronary arteries, under certain circumstances,
does not always produce clinical symptoms or
myocardial damage.' This apparent inconsistency between the presence of long-standing
obstructive lesions and the absence of pathologic or clinical evidence of myocardial damage
has been dispelled by the demonstration in
man of larger than normal interarterial coronary anastomoses.2 These anastomoses serve
From the Medical Research Department of the
Yamins Research Laboratories and the Pathology
Department of the Beth Israel Hospital, and the
Departments of Medicine and Pathology, Harvard Medical School, Boston, Mass.
This investigation was aided by grants from the
Life Insurance Medical Research Fund, the U. S.
Public Health Service, the Patrons of Research an(1
the Sidney R. Green Heart Research Fund of the
Beth Israel Hospital, Boston, Mass.
797
Circulation, Volume IV, December. 19.51
798
INT7NRARTERIAL CORONARY ANASTOMOSES IN HUMAN HEART
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has been gained and several factors affecting
their development have been identified.
The subject of coronary interarterial anastomoses has been investigated in many different ways since 1669 when Lower34 stated, "The
vessels which carry blood to the heart come
together again, and here and there communicate by anastomoses." Simple dissections of
coronary vessels in both human and animal
hearts have been supplemented by injections
with various materials.4-14, 16-27, 29, 32, 33, 36-41, 45,
51, 55, 64, 67, 68, 71, 72, 74-121 Water, air, suet, Max,
oils, turpentine, dyes, inks, starch, bacteria,
Wood's metal, mercury, iron, bismuth and lead
compounds, microscopic glass spheres, radioactive erythrocytes, celloidin, gelatin, latex and
liquid nylon have been used. For the most
part, these studies have confirmed and led to
the general acceptance of the idea that interarterial coronary anastomoses exist. Occasional
disagreements 81, 82, 85, 87-89, 94, 95 have resulted
largely from differences in materials or technics
of injection, from anatomic variations among
species, from varying pathologic conditions in
the same species or, most frequently, from
differences in interpretation of results.
All investigators agree that, when watery
solutions or suspensions of very fine particles
like India ink are injected into one coronary
artery, they appear promptly in the other coronary arteries and their branches.'22 Such materials, however, traverse the capillary bed and
reach the coronary venous system. They cannot, therefore, be used to determine at which
level (artery, arteriole or capillary) intercoronary arterial communications occur.
To circumvent this difficulty it is necessary
to use injection masses which do not traverse
the capillary bed.7 51,109 The lead-agar mass
employed in this investigation109 was regularly
found in vessels as small as 40 microns in
internal diameter, irregularly penetrated as far
as vessels from 40 to 10 microns in diameter but
was not found in vessels under 10 microns in
diameter. These measurements of vessel size
were made on stained microscopic sections prepared from tissue fixed in formalin and embedded in paraffin; they are therefore subject to a
correction of about 50 to 100 per cent for
shrinkage from the fresh unfixed state. The
actual diameter of injected vessels is less important than their nature (i.e., arteriole, capillary or venule): with this method the leadagar mass did not enter the capillary bed and
did not appear in the venous system.
The level of penetration of injected material
probably depends on many other physical properties in addition to the size of the particles.
Although most of the individual particles of
lead phosphate in the lead phosphate-agar mass
measured about one micron in size and exhibited brownian movement in aqueous suspension, a suspension of them did not penetrate vessels many times larger. Differences in
extent of penetration of the mass in different
hearts, from "stumpy" injection of only the
larger arterioles to very "fine" injections with
filling of smallest arterioles could be produced
by purposeful variations in technic.
Our earlier studies2' 109, 123 on smaller numbers of hearts injected by this technic revealed
interarterial coronary anastomoses in 10 to
22 per cent of human hearts that were otherwise normal at autopsy. The occurrence of
anastomoses was found to be unrelated to age
and sex, but it was definitely increased in the
presence of valvular disease and coronary artery narrowing. Anastomoses were always
found in hearts with old complete coronary
artery occlusions. These observations have been
confirmed by other workers."'1 117,117
METHOD AND MATERIAL
An autopsy series of 1271 unselected human hearts
has been studied at the Beth Israel Hospital, Boston,
by a uniform injection plus dissection technic,'09
Briefly this method consisted of the following steps:
(1) Injecting radiopaque lead-agar mass of different colors into the main coronary arteries at a pressure of 150 to 200 mm. Hg.
(2) Unrolling the heart so that the coronar'y
arterial tree lay in one plane.
(3) Taking a roentgenogram of the unrolled heart.
(4) Carefully dissecting and opening the coronary
arteries, using the roentgenogram as a guide.
With this method the demonstration of narrowings, occlusions and anastomoses in the coronary
arteries was greatly facilitated. The technic of unrolling the heart reduced the difficulty in following
the three-dimensional course of the vessels on a
two-dimensional film.
Criteria were established for the determination
of anastomotic communications. It was found that
the roentgenograms alone could not be relied upon
P. M. ZOLL, S. WESSLER AND M. J. SCHLESINGER
to prove the existence of such communications. Overlapping vessels, like the bare branches of adjacent
trees,5' often deceptively gave the appearance
of intercommunications. Conversely, anastomoses
could be clearly demonstrated on careful dissection
which were not visible on the roentgenogram. On
the basis of careful dissection three types of proof
of anastomoses were accepted: (1) demonstration
of a continuous, stained, endothelial-lined connecting channel filled with mass between two coronary
arteries; (2) presence of injection mass of any color
distal to a complete occlusion and (3) visualization
of a mixture of color in the injection mass.
(1) Demonstration of a Continuous, EndothelialLined, Connecting Channel Filled with Mass between
799
was important in supporting the validity of the
other two methods of demonstrating interarterial
anastomoses.
(2) Presence of Injection Mass of Any Color Distal
to a Complete Occlusion. Since a complete coronary
artery occlusion prevented direct filling of the peripheral vascular tree, mass of any color found beyond
an occlusion must have gotten there by collateral
pathways. Interarterial anastomoses could be
demonstrated by finding mass of the same color
both proximal and distal to an occlusion.
(3) Visualization of a Mixture of Colors in the
Injection Mass. Since the color of the injected mass
identified its source, mixture of colors necessarily
indicated a connecting pathway between two coro-
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FIG. 1. Colored roentgenogram of injected heart (A 43-128) with multiple coronary artery occlusions and extensive interarterial coronary anastomoses. Anastomoses are demonstrated by (a) grossly
dissectible channel between two coronary arteries; (b) injection mass of any color distal to complete
occlusion; (c) mixture of colors of injection mass. (The use of color in this illustration was made
possible by a grant from Wyeth, Incorporated, to the publication fund of the American Heart
Association.)
Two Coronary Arteries. Communications were proved
to be unquestionable interarterial anastomoses only
when a continuous, intact, vascular pathway could
be demonstrated connecting two coronary arteries.
Grossly dissectible anastomoses were demonstrable
when the vessel was about 0.2 mm. in diameter or
larger, but vessels, less than 0.5 mm. in diameter
were not readily opened. Smaller anastomoses 60
to 70 microns in diameter could be traced along
their entire course by laborious study under the
dissecting microscope in tissue cleared by the Spalteholz technic'00 or by reconstruction of a complete
series of microscopic sections. Vessels of this caliber
were not visible on the roentgenogram. Indisputable
demonstration of grossly dissectible pathways in this
way was possible in only about one-fifth of the
hearts in which anastomoses were accepted as present. Although somewhat infrequent, this method
nary arteries. This was the most common method by
which interarterial communications were demonstrated. The validity of accepting mixture of colors
as evidence of an interarterial anastomosis rather
than of an artificial extravascular connecting channel
or of a common capillary bed between two arteries
depended upon three lines of supporting evidence:
(a) the absence of gross or microscopic evidence of
extravasations of mass; (b) the absence of mass in
capillaries or veins and (c) the frequent gross or
microscopic demonstration of a continuous, indisputable endothelial-lined vessel connecting two coronary arteries in hearts in which mixture of colors
was found. Figure 1 shows the colored roentgenogram of an injected heart in which intercoronary
arterial anastomoses were demonstrated by all three
methods.
Although areas of even slight narrowing stood
800
INTERARTER1AL CORONARY ANASTOMOSES IN HUMAN HEART
permitted classification according to the presence
or absence of anastomoses, cardiac hypertrophy,
valvular and congenital heart disease, coronaryl
artery narrowings and occlusions and cor pulmonale.
Tabulation was also made of clinical data of possibly
related significance such as age, sex, arterial hypertension, pulmonary, renal and metabolic diseases,
chronic wasting disease, prolonged cardiovascular
collapse, surgical operations, duration of terminal
illness and anemia.
out on the film as irregularities in the shadow of
the injected mass, the presence and extent of suspected coronary artery narrowings occlusions were
determined primarily in the dissection, Mwhen the
arteries were commonly opened down to small
branches. The solidified mass found in them as a
cast of the lumen facilitated determination of the
degree of narrowing or the presence of complete
occlusions. The staining of the intima by d(ye diffused
from the mass also aided dissection of small or
or
WITH CORONARY ARTERY DISEASE
NO CORONARY ARTERY DISEASE
COR
GROSSLY VALVULAR
NORMAL DISEASE PULMONALE
NARROWING
slight moderate marked
80
WITHOUT
CARDIAC
HYPERTROPHY
OCCLUSION
1
old
recent
60-
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40-
E
101 91
5
5
° 100i
WITH
CARDIAC
801
HYPERTROPHY
No.
*
totl
24 19
27 17
numb or in
*
too few for separate analysis
all coes grouped together without
reference to
anemIa or
33
8
* without
anemIa
_
m
hypertrophy
with anemia
FIG. 2. The incidence of intercoronary arterial anastomoses in relation to anemia, cardiac hypertrophy, valvular and coronary artery disease.
narrowed vessels. At sites of complete occlusion
neither mass nor stained intima w-as found.
After dissection of the arteries to determine
anastomoses and the extent of coronary narrowing
and occlusion, the mavocar(lium, valves and both
cardliac surfaces were carefully examined in each
heart and suitable sections taken for microscopic
study. From about one-half of the total series of
injected hearts a large number of individually
labeled sections from exactly localized sites in the
heart were made in order to permit closes correlation
of the local histopathology- of the my-ocardium with
changes in the coronary arteries.
Of the 1271 injected hearts available, 1050 w-ere
selected for the present study on intercoronaryarterial anastomoses. The qualifications for selection were an injection adequate to determine interarterial anastomosis and other (letaile(l postmortem
and clinical data .* The cardiac pathologic data
of simplication, !92 of the cases with
all the above categories were
omitted from the present series b)eca.use they exhibite(l coml)iinations of valvular heart(disease and cor*
For
purposes
ale(uate (lata in
onary
artery pathology.
RESULTS
Table 1 presents the complete data on these
1050 hearts in all their subdivisions; some of
the groups are presented individually in tables
2 to 5. Of this selected group, 480 (46 per
cent) showed interarterial coronary anastomoses. Figure 2 presents an analysis of all hearts
with anastomoses with respect to the relative
frequency of the groups into which these 480
cases fall.
The Normal Heart and Coronary Artery Anastomoses
Criterion of the Normal Heart. Of the 1050
hearts in the series, only 244 (23 per cent) were
considered as a normal, control group (table 1).
A.ll these hearts weighed less than 350 Gm.
and did not showv any valvular or congenital
lesions, right ventricular hypertrophy
nary
artery narrowing
or
or
coro-
occlusion. Heart
P. M. ZOLL, S. WESSLElR AND M. J.
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weights under 350 Gm. w-ere considered normal
for reasons which will be discussed in the section on cardiac hypertrophy. Hearts with very
little or questionable coronary artery narrowing
were rejected from this normal, control group.
This was done in order to preserve the integrity of the normal, control group which was
to serve as a standard of comparison for the
entire series. It was deemed preferable thus
to include some almost normal hearts in the
group with slight coronary artery narrowing
rather than to include them in the normal,
control group.
Of the 244 normal hearts rigidly selected in
this way, 55 (23 per cent) showed interarterial
coronary anastomoses (table 1). This figure
is similar to that reported in an earlier study.123
No correlation was found between the imcidence of coronary artery anastomoses and anatomic variants such as the relative length of
right and left circumflex coronary arteries'24
or the presence of a conus artery.'23
Anemia and Coronary Artery Anastomoses
In an effort to disclose some clinical feature
that might be related to coronary artery anastomoses, the clinical records of the entire group
of patients with normal hearts were reviewed.
The following factors were evaluated: (1) age,
(2) sex, (3) arterial hypertension, (4) severe
pulmonary disease, (5) renal disorders, (6) thyroid or other metabolic diseases, (7) chronic
or debilitating disease, (8) prolonged cardiovascular collapse, (9) surgical procedures, (10)
duration of terminal illness and (11) anemia.
Of all these factors a definite correlation was
found only between coronary artery anastomoses and anemia.
Criterion of Anemia. Determination of anemia was based on hematocrit or hemoglobin
levels. Hemoglobin determinations were made
by the Sahli calorimetric or Evelyn photoelectric technics; 15.5 Gm. hemoglobin per cent
was considered 100 per cent hemoglobin. Hematocrit determinations w-ere made by adequate
centrifugation of blood in Wintrobe tubes.
When necessary, hematocrit levels were
equated with hemoglobin percentages by considering a hematocrit of 45 per cent equivalent
to 100 per cent hemoglobin.
All patients in the series were classified with
SCHLESINGER80
801
respect to anemia as follows: (1) patients with
hemoglobin levels of 75 per cent or more were
placed in a nommanemic group; (2) those with
hemoglobin levels of 70 per cent or less were
placed in an anemic group; (3) the remainder
with intermediate or indeterminate levels were
discarded from the analysis of anemia. This
last group consisted of patients with hemoglobin levels between 70 and 75 per cent and
those with marked hemoglobini fluctuations. A
few cases were also discarded in which hematologic data were not available or were unreliable. Finally all patients in whom aniemia
had been present for five days or less before
death were also discarded. Experimental studies
on the production of intercoronary arterial anastomoses in the dog12m and the pig3 offer some
support to this choice of a five (lay limit.
The correlation demonstrated between anemia and anastomoses was not altered significantly by moving the criterion for anemia to
75 or 80 per cent hemoglobin, or by enlarging
the intermediate, discarded group to include
levels of 70 to 80 per cent hemoglobin. Such
changes, however, redlueled the number of cases
available for analysis of other factors and
thereby lowered the statistical validity of the
data.
Effect of Anemia. Of the 244 patients with
normal hearts, 101 were in the nonanemic category; 91 showed anemia as defined above. These
192 cases were used inl a correlation of anemia
and anastomoses (table 2 and fig. 2). Coronary
artery anastomoses were present iil only nine
(9 per cent) of the nonianiemic control group
and in 35 (39 per centt) of the anemic group.
This difference is highly significant statistically
as measured by the chi square test or standard
error of difference. *126 Further analysis of the
group of 91 cases with anemia was carried
out to determine the relative effect of varying
degrees of anemia upon anastomosis. No significant difference was found in the incidence of
anastomoses in groups with (liffering degrees of
anemia. For example, of 52 cases with hemoglobin levels consistently below 60 per cent,
16 (31 per cent) showed anastomoses; of 31
cases with anemia between (60 and 70 per cent
* Differences were considered to be statistically
significant if they were 2.5 times the standard error
of the difference.
802
INTERARTERIAL CORONARY ANASTOMOSES IN HUMAN HEART
TABLE 1.-Incidence of Interarterial Coronary A nastomoses
inl All
Groups of Total Series
Normal Weight
Anemia
Cardiac Hypertrophy
HeartswihAatmssHrs
Total Number
Hearts
Number |Per Cent
Total Number
Dissectible
Hearts with Anastomoses
Number
Per Cent
Dissectible
A. No Coronary or Valvular Disease
Nonanemic ............
Anemic ..............
101
91
9
35
9
39
0
4
70
50
18
14
26
28
0
0
Total* ...............
244
55
23
4
153
38
25
0
B. Valvular Disease
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Nonanemic
5
1
t
0
32
9
28
1
Anemic................
Total* .13
5
3
4
t
0
0
19
6
2
62
23
32
37
3
31
C. Slight Coronary Artery Narrowing
Nonanemic .28
Anemic .19
5
2
18
11
1
0
27
17
3
6
11
39
0
0
Total* .65
11
17
2
57
13
23
0
D. Moderate Coronary Artery Narrowing
Nonanemic .19
Anemic...............
Total*
....
15
3
5
16
33
1
1
24
19
7
4
29
21
2
0
44
11
25
2
56
14
25
2
E. Marked Coronary Artery Narrowing
Nonanemic
Anemic ......
Total*
.
8
3
5
2
63
t
0
0
33
8
18
7
55
88
3
2
19
12
63
1
47
26
55
5
F. Coronary Artery Occlu.ion
Totalt.................
275
262
95
72
G. Cor
Pulmonale
Totalt...............
1.5
11
73
3
Grand Total of Entire
Series ..
1050
480
46
94
*
Totals include additional cases with intermediate or indeterminate hemoglobin levels.
t Too few in number.
t All hemoglobin levels and weight groups combined in single tabulation.
hemoglobin, 15 (48 per cent) showed anastomoses.
The small group of nine patients without
anemia in whom the hearts were normal but
nevertheless showed coronary artery anastomoses was reinvestigated in detail. Severe pul-
P. M. ZOLL, S. WESSLER AND M. J. SCHLESINGER
monary disease was found in six of them. The
possible relation of pulmonary disease to coronary artery anastomoses is discussed below.
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Cardiac Hypertrophy and Coronary Artery Anastomoses
Criterion of Hypertrophy. A review of the
literature on cardiac hypertrophy did not disclose any simple, generally accepted criterion
for this factor.27-"35 The 103 hearts in the
entire group which weighed 300 Gm. or more
but were otherwise normal and which came
from nonanemic patients were subdivided according to weight into four comparable groups
of (1) 450 Gm. or more, (2) 449 to 400 Gm.,
(3) 399 to 350 Gm. and (4) 349 to 300 Gm.
TABLE 2.-The Incidence of Interarterial Coronary
Anastomoses in Relation to Anemia in Cases without
Cardiac Hypertrophy, Valvular or Coronary Disease
Anastomoses
Total
Hemoglobin Levels
Absent
Nonanemic ..........
Anemic .............
Total
92
56
148
803
cent) of the 50 hypertrophied hearts from anemic patients (fig. 2). This incidence does not
differ significantly from the 26 per cent in the
group of cardiac hypertrophy without anemia
or from the 39 per cent in the normal hearts
with anemia. Anemia and cardiac hypertrophy
individually were associated with an increased
incidence of anastomoses in the human coronary artery system, but combination of the
two did not show an additive effect with a still
higher incidence.
Valvular Heart Disease and Coronary Artery
Anastomoses
Criterion of Valvular Disease. Valvular heart
disease without coronary artery disease was
TABLE 3.-The Incidence of Interarterial Coronary
Anastomoses in Relation to Cardiac Hypertrophy in
Cases without Anemia, Valvular or Coronary Disease
Heart Weight
Total
Number
of Hearts
Present
9 (9%)
35 (39%)
101
91
44
192
(table 3). The frequency of anastomoses was
high and constant in each of these small groups
above 350 Gm. and dropped sharply in the
group below 350 Gm. The entire group of 70
hearts above 350 Gm. may therefore be considered homogeneous. In this way the selection
of a heart weight of 350 Gm. or more was supported as the criterion for cardiac hypertrophy
throughout this study.
Effect of Hypertrophy. Among the 1050 hearts
in the series were 153 which were normal in all
pathologic respects except for hypertrophy as
above defined. In the 70 hearts from this group
that came from patients without anemia, the
incidence of interarterial coronary anastomoses
was 26 per cent (fig. 2). This incidence is
significantly higher (2.9 times the standard
error of the difference) than the 9 per cent
in the normal, control group without hypertrophy.
Effect of Anemia Plus Hypertrophy. Coronary
artery anastomoses were found in 14 (28 per
450 Gm. or more
449 to 400 Gm ........
399 to 350 Gm ........
349 to 300 Gm ........
25
21
24
33
Hearts with
Anastomoses
Number
Per Cent
6
6
6
24
29
25
6
2
found in 75 hearts. The valves presented definite organic stenosis, insufficiency or a combination of defects. Only hearts with valvular
disease thus established at autopsy were included in this category.
Effect of Valvular Disease. Coronary artery
anastomoses were present in 27 (36 per cent)
of all 75 hearts with valvular disease (table 1).
This group is heterogeneous in that hypertrophy or anemia or both were present together
with the valvular disease in all but five cases.
The largest homogeneous subgroup of 32 hearts
with valvular disease plus hypertrophy from
nonanemic patients (table 1 and fig. 2) showed
an incidence of anastomoses of 28 per cent,
which is essentially the same as the 26 per
cent in hearts with hypertrophy alone. Furthermore, upon addition of anemia to valvular
disease and hypertrophy, a similar incidence
of anastomoses of 32 per cent in 19 cases was
found (table 1 and fig. 2). The three factors of
anemia, hypertrophy and valvular disease,
804
INTERARTERIAL CORONARY ANASTO1MOSES IN HUMAN HEART
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whether taken singly or in any combination,
showed similar frequencies of anastomoses, from
26 to 39 per cent, without additive effect (fig. 2).
Coronary Heart Disease and Coronary A rtery
Anastomoses
Criterion of Coronary Artery Narrowing and
Occlusion. All the hearts in the series were
classified in five categories according to the
condition of the coronary arteries: (1) 472
hearts without any coronary artery narrowing,
already discussed under the various headings of
the normal heart, anemia, hypertrophy and
valvular disease; (2) 122 hearts with slight
coronary artery narrowing; (3) 100 hearts with
moderate coronary artery narrowing; (4) 66
hearts with marked coronary artery narrowing,
but without complete occlusions; (5) 275 hearts
with complete coronary artery occlusions, old
or recent. In 15 additional hearts cor pulmonale
was the primary pathologic condition; in them
the degree of coronary artery narrowing ranged
from none to moderate and was disregarded. *
This classification of the degree of coronary
artery disease was based on judgments by
different observers at the time of dissection
and subsequently on re-examination of the
roentgenogram of the injected heart. Multiple,
independent observations were made frequently
on individual hearts by several observers with
close agreement. In some of the hearts the
internal diameters of the major vessels were
measured by a series of graduated probes, so
that the degree of reduction in diameter at
sites of narrowing was quantitatively determined by comparison with adjacent zones. It
was found that estimates of slight narrowing
correspon(led to a reduction in diameter approximately of 25 per cent or less; marked
narrowing was equivalent to reductions of 75
per cent or more. The term "occlusion" always
denoted complete occlusion of a coronary artery; a complete break in the continuity of
the lumen was demonstrated in the dissection
by the absence of mass or colored intima in
such areas. Occlusions were further classified
* It Bill be noted that there are no hearts with
comblinat ions of coronary anird valvular disease; all
such hearts were discarded from the series to simplifthe analysis.
as recent or old largely on the basis of their
gross appearance. Microscopic estimation of
the duration of the occlusive process auras made
only in relatively few, selected instances.
Effect of Coronary Artery Narrowing. All 288
cases with coronary artery narrowing were classified according to the degree of narrowing, the
presence of hypertrophy and anemia (fig. 2).
The incidence of anastomoses in the groups
with slight and moderate narrowing did not
differ significantly from their appropriate comparison groups without narrowing. Every subdivision with marked narrowing, however,
showed a significantly high incidence of coronary artery anastomoses: anastomoses were
found in 58 per cent of all hearts with marked
coronary artery narrowing. Anastomoses were
found in only 26 to 39 per cent, however, of
hearts without coronary narrowing to which
were added the factors of anemia, hypertrophy
and valvular disease, singly or ill combination.
Again, anemia and hypertrophy were not effective in increasing coronary artery anastomoses
in the presence of marked coronary artery
narrowing, just as combinations of them were
not additive in the absence of marked coronary
narrowing.
Effect of Recent Coronary Artery Occlufsions.
Among the 275 hearts with complete occlusions
of the coronary arteries were 121 with one or
more points of recent occlusion (table 4 and
fig. 2). Interarterial coronary anastomoses were
demonstrated in 108 (89 per cent) of these
121 hearts. Anemia and cardiac hypertrophy
were not important in the development of anastomoses in this group.
More than one recent occlusion was present
in 27 of these 121 hearts, so that the total
number of recent occlusions was 1 63 (table 4).
Analysis of the local anatomic relation of the
anastomoses to each of these 163 indiviidual
recent occlusions throws light on the mechanism of development of interarterial anastomoses. Anastomotic filling of those branches of
the coronary arteries directly peripheral to recent occlusions was demonstrated only in 110
of the 163 instances (68 per cut). Many of the
recent coronary artery occlusions were clearly
superimposed on the site of previous marked
coronary artery narrowing. \Iarked narrowing
P. M. ZOLL, S. WESSLER AND M. J. SCHLESINGER
805
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heart. Anastomoses were demonstrated in the
coronary arteries directly distal to all but 13
of these 349 sites of old occlusion (96 per cent).
Even when the instances of old occlusions found
in hearts with both recent and old occlusions
were added, the incidence of anastomoses directly distal to old occlusions remained high
at 91 per cent (table 4).
The special means of demonstrating anastomoses in hearts with coronary artery occlusions
by finding injection mass of the same color on
both sides of an occlusion was the sole evidence
of anastomoses in only 12 (8 per cent) of these
154 hearts. It was, therefore, not a significant
factor in the high incidence of anastomoses in
alone without occlusion has already been shown
to be associated with an incidence of 58 per
cent of anastomoses. Hence it appears likely
that the localized anastomoses found distal
to recent occlusions were induced in most instances by previous coronary artery narrowing.
Effect of Old Coronary Artery Occlusions. The
group of 154 hearts with at least one old occlusion and no recent occlusions in the coronary artery tree comprised 15 per cent of the
total series of 1050 hearts. Intercoronary anastomoses were present in every one of these
154 hearts. In the larger group of 236 hearts
with old coronary artery occlusions (including
82 with recent occlusions as well), all but three
TABLE 4.-The Incidence of Interatterial Coronary Anastomoses in Hearts with Coronary Artery Occlusions
Anastomoses Distal to
Occlusion
Anastomoses in Heart
Group
Number of Hearts
Number
Hearts with Recent Occlusions
Only
29
39
---1
---l
Number of
Occlusions
Per Cent
Number
Dissectible
74
2
50
21
113
Number
29
Per Cent
58
---1
Recent Occlusions
82
Hearts with Recent Plus Old Occlusions
79
96
81
72
Old Occlusions
237
I-
Hearts with Old Occlusions Only
_________________
-
-
_________________________________-
Total of Hearts with Occlusions
154
-
-
275
-
-
.
per
84
154
100
49
349
336
96
262
95
72
749
644
86
1
cent) showed interarterial coronary
anastomoses (table 4). In these three exceptional instances existing anastomotic pathways
may have been blocked by the terminal acute
occlusion. This almost invariable occurrence of
anastomoses in hearts with old coronary artery
occlusions is striking, whether it be compared
with the incidence of anastomoses in normal
hearts (9 per cent), in hypertrophied hearts
(26 per cent), in hearts from patients with
anemia (39 per cent), in hearts with marked
coronary artery narrowing (55 per cent), or in
hearts with recent coronary artery occlusions
(74 per cent).
In the 154 hearts with old coronary artery
occlusions there were 349 separate points of
old occlusion, or over two old occlusions per
(99
198
__
I-
hearts with old occlusions. Similarly, anemia
was infrequent (13 per cent) in the 154 patients
with old coronary artery occlusions and, therefore, not significant in producing all the anastomoses.
Cor Pulmonale and Coronary Artery Anastomoses
Criterion of Cor Pulmonale. Uncomplicated
cor pulmonale was present in 15 of the 1050
hearts studied. In these 15 instances additional
factors that might produce anastomoses, such
as anemia, valvular disease, marked coronary
artery narrowing or occlusion, were absent.
Relative right ventricular hypertrophy, usually
secondary to pulmonary fibrosis, was taken
as the distinctive criterion of cor pulmonale,
INTERARTERIAL CORONARY ANASTOMOSES IN HUMAN HEART
806
even with a normal total heart weight. All
these patients had suffered from severe, chronic
pulmonary disease. In these 15 hearts the right
ventricle measured 5 mm. or more in thickness
or was greatly enlarged and dilated. The roentgenogram of the unrolled heart showed clearly
the relative size and density of the soft tissue
shadows of the right and left ventricles. In this
way it provided valuable confirmatory data to
the observations made at the autopsy table
concerning right ventricular hypertrophy.
Effect of Cor Pulmonale. Anastomos3s were
present in 11 (73 per cent) of these 15 hearts
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TABLE 5.-Incidence of Etiologic Factors in 480 Hear'ts
with Interarterial Coronary Anastoinoses
Incidence of
Total Incidence
Factor as
of Factor, Alone
or Combined Single Condition
\Iarked Coronary Artery Disease (complete occlusion or
marked narrowing)
Slight to Moderate Coronary Artery Narrowing
Cardiac Hypertrophy
Antemortem Anemia
Valvular Heart Disease
Cor Pulmonale
Grossly Normal Hearts
Number
Per
Cent
Number
Per
Cent
300
63
89
19
49
10
8
2
180
38
24
6
2
18
35
1
0
4
7
0
0
9
2
114
27
11
(table 1 and fig. 2). Iespite the larg4 e standard
error
in this small group, there is
a
si tatistically
significant increase in the incidence of anastomoses over the 9 per cent seen in nor mal hearts
without anemia, 26 per cent in hypgertrophied
hearts and 11 to 29 per cent in h(earts with
slight to moderate coronary artery ]narrowing.
Cor pulmonale thus is associated fith an increase in interarterial coronary anm astomoses.
Relative Frequency of Factors Inducirig A nasto-
lated in two ways: (1) their total incidence,
whether they occurred alone or in (.oml)ina.tiollt,
and (2) their individual incidence in hearts with
a single, uncomplicated factor. Marked coronary artery disease, cardiac hypertrophy and
aniemia were the most frequent etiologic factors.
The relative frequency of these factors inl
hearts with anastomoses reflects not only their
etiologic effect in inducing anastomoses, but
also their frequency in this particular series of
1050 hearts. The individual efficacy of these
factors in inducing anastomoses has already
been considered in the presentation of the
percentage of hearts with anastomoses inl the
various groups. Both tabulations indicate the
preponderant role of marked coronary artery
disease in inducing interarterial (coronoar y
anastomoses and the less marked effects of
cardiac hypertrophy and anemia.
Grossly Dissectible AInastomoses
Grossly dissectible communicating pathways
were found in 94 hearts (20 per cent) of the
480 hearts with anastomoses (table 1); 72 of
them occurred in the 275 hearts with coronary
artery occlusions. More particularly, they were
found in 70 (30 per cent) of the 236 hearts
'with old coronary artery occltusions and in
only two (5 per cent) of the 39 hearts with
recent occlusions alone. This latter incidence is
lower than the 9 per cent found in the 66
hearts with marked coronary artery narrowing
and the 20 per cent found in the 15 hearts with
cor pulmonale. Grossly dissectible anastomoses
were of a similar low frequency in the remainder
of the series, occurring in four (4 per cent) of
the 100 hearts with moderate coronary artery
narrowing, in two (2 per cent) of the 122 hearts
with slight coronary artery narrowing, in three
(4 per cent) of the 75 hearts with valvular
disease and in four (1 per cent) of the 397
remaining hearts in the series without coronary
or valvular disease (table 1).
moses
All 480 hearts with interarterial coronary
anastomoses were analyzed with resi )ect to the
relative frequency of the seven grroups into
which these cases fell (table 5). Siinee many
hearts presented combinations of eti ologic factors, the incidence of these factors was tabu-
Myocardial Histopathology
Multiple, individually labeled microscopic
sections from precisely localized areas of the
myocardium were studied in 509 of the 1050
hearts in this series. These 509 hearts are not
consecutive and do not form a representative
P. M. ZOLL, S. WESSLER AND Ml. J. SCHLESINGER
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sample of the entire group of injected hearts.
Nevertheless, certain broad relations between
anastomoses and histopathologic changes in
the myocardium could be determined. M\icroscopic abnormalities noted included myocardial
degeneration, necrosis, inflammation and fibrosis Although these lesions varied considerably,
qualitatively and quantitatively, in different
hearts, they were grouped together and are
presented in summary form here insofar as
they are pertinent to the problem of coronary
artery anastomoses.
As might be expected, few of the grossly
normal hearts without hypertrophy, valvular
or coronary disease showed histopathologic abnormalities. Nevertheless, like anastomosis, histopathology was significantly more frequent in
the anemic hearts than in the nonanemic hearts
of this group. In general, a parallel increasing
association was found between hypertrophy,
valvular and coronary lesions and the presence
of histopathology and anastomosis.
Of 319 hearts with histopathology, however,
interarterial anastomoses were absent in 98.
Conversely, it was of particular interest to
find seven hearts without any microscopic myocardial pathology among the 114 with one or
more complete old occlusions in which multiple
microscopic sections were studied. In each of
these instances there were found well-developed, extensive interarterial coronary anastomoses which may have protected the myocardium from the effects of arterial occlusion.
Time Necessary for Development of Anastomoses
following Sudden Occlusion of a Coronary Artery
The relatively low incidence (58 per cent)
of coronary artery anastomoses directly distal
to recent coronary artery occlusions in
comparison with the 96 per cent incidence of
anastomoses directly distal to old occlusions
suggests that the time interval between the
occurrence of the recent vascular occlusion and
death was insufficient in some instances for
the development of compensatory anastomoses.
Valuable information concerning the time
necessary for the development of collateral circulation might be obtained by relating the
age of a recent complete occlusion to the pres-
807
ence or absence of an anastomosis associated
with it.
In such a study it would be necessary to
know the age and rate of development of the
recent occlusion and how much narrowing was
present in the vessel before the recent occlusion
occurred. Gross observations are too crude to
establish these facts. Numerous microscopic
sections, preferably serial sections, through
each zone of recent occlusion would provide
such reliable information, but they were not
available in the present series of hearts.
An attempt was made to fix the time of the
terminal fresh coronary artery occlusion from
the clinical record. As might be expected, however, it was unsuccessful because correlations
between maj or episodes of cardiac pain and
coronary artery occlusion are unreliable. Such
episodes of pain, even associated with myocardial infarction, may occur without concomitant fresh occlusion in the coronary artery
tree and fresh coronary artery occlusions, furthermore, may occur without clinical mani-
festations?136
In this series clearly defined, well-timed clinical episodes appeared in only 73 of the 121
patients dying with recent coronary artery occlusions. Furthermore, most of the 73 also
had multiple, prolonged attacks of cardiac pain.
Consequently, we were not able in this study
to determine the rate of development of coronary interarterial anastomoses in man.
DISCUSSION
A definite, statistically significant relationship has been found between a number of
factors and the development of human intercoronary arterial anastomoses. In the absence
of these stimulating factors less than 10 per
cent of human hearts presented anastomoses.
It is also suggested that the incidence of anastomoses in the normal human heart would be
still lower if all etiologic factors were known.
Thus it is becoming more firmly established
that, functionally at least, the coronary arteries in the human heart are end-arteries. It
is also clear that' under a variety of stimuli
the flexible coronary arterial system readily
develops a functioning internal anastomotic
collateral circulation to compensate for a
808
INTERARTERIAL CORONARY ANASTOMOSES IN HUMAN HEART
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relative insufficiency of blood. Relative insufficiency may originate in the blood itself
(aneemia), in the aeration of the blood (pulmonary disease), in the myocardium (hypertrophy), in the endocardium (valvular disease)
or in the coronary arteries themselves (coronary
atherosclerosis).
The previous observation that marked narrowing and complete occlusion of the coronary
arteries are most important factors in the production of interarterial coronary anastomoses
has been firmly established. Their effectiveness
is seen in the high incidence of anastomoses
and in the frequency of large, grossly dissectible
interarterial pathways under these conditions,
as well as the great frequency of marked coronary artery disease in hearts with anastomoses.
Slight or moderate coronary artery narrowing
is much less effective. The experimental production of intercoronary anastomoses following
narrowing and occlusion of the coronary arteries by surgical ligation in pigs and dogs' 125
led to similar conclusions concerning these factors. Furthermore, the functional significance
of such intercoronary anastomoses was demonstrated experimentally in the prevention of
death and the reduction of myocardial damage
following complete coronary occlusion.
The detailed histopathologic studies of human
hearts with marked narrowing and complete
occlusion of the coronary arteries indicate the
similar functional importance of such anastomoses in the human heart. The increasing frequency of hearts with myocardial damage with
increasing degrees of coronary artery obstruction was anticipated. The few hearts, however,
with complete old coronary artery occlusions
but without any histopathology in the multiple
microscopic sections illustrate pointedly the
protective effect of the anastomoses. In these
hearts, the development of interarterial coronary anastomoses during gradual coronary artery narrowing must have been so adequate as
to prevent organic muscle damage even with
final complete occlusion of an artery. These
observations find their occasional clinical corollary in the absence of cardiac pain or other
symptoms after a proved acute coronary artery
occlusion.136 In these instances, at least, the
stimulus for interarterial coronary anastomoses
did not lead also to irreversible myocardlial
lamage.
Besides marked coroniary artery disease, the
factors of hypertrophy and of anemia have each
been demonstrated to be associated individually with an increased incidence of intercoronary anastomoses. The addition of cardiac hypertrophy or anemia to other factors did not
materially affect the incidence of anastomoses.
The absence of a summative effect of several
factors was unexpected. It is possible that some
underlying fundamental mechanism such as
cardiac anoxia is common to all the factors
concerned. This mechanism may be activated
by any single factor, but is not activated to a
greater degree or does not produce a greater
effect when stimulated by several factors in
combination. Because of the small numbers of
hearts available in the various subgroups, a
small additive effect might not have been statistically apparent in the present analysis. Furthermore, in any statistical analysis based on
the "null hypothesis," failure to demonstrate
"significant" differences does not prove their
absence."37
The data are inadequate to establish an association of valvular disease per se with increased
intercoronary anastomoses, since most of the
hearts with valvular disease also showed cardiac
hypertrophy. Valvular disease plus cardiac hypertrophy showed the same incidence of ansastomoses as hypertrophy alone. Nevertheless,
valvular disease alone may be a factor inducing
interarterial coronary anastomoses; like anemia
and coronary artery disease, an additive effect
upon anastomoses may not be demonstrable
when it is combined with cardiac hypertrophy.
In half of the 27 hearts with chronic valvular
disease in which coronlary artery anastomoses
were present, there was also marked right ventricular hypertrophy, indistinguishable from
that resulting from primary pulmonary disease.
In these hearts the mitral valve was usually involved. The development of anastomoses in
this group may result from: (1) valvular disease
itself, if it is indeed a factor capable of stimulating anastomoses; (2) cardiac anoxia on the
basis of diminished oxygenation of the blood
from pulmonary insufficiency; or (3) cardiac
P. M. ZOLL, S. WESSLER AND AM. J. SCHLESINGER
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hypertrophy with increased need for blood by
the enlarged myocardium.
In like manner, the increased intercoronary
arterial anastomoses found in cor pulmonale due
to pulmonary disease may result from right
ventricular hypertrophy or cardiac anoxia secondary to pulmonary insufficiency. These two
mechanisms may also be involved in the six
"normal" hearts with coronary artery anastomoses but without cardiac hypertrophy which
came from patients with marked pulmonary
disease, but without anemia. If the mechanisms
were more clearly established by which primary
pulmonary disease stimulated the development
of coronary artery anastomoses, the number of
"normal" hearts with unaccountable anastomoses could be reduced to three instead of nine in
the series of 1050 hearts. Furthermore, the
finding of unexplained myocardial histopathology in a few grossly normal hearts from patients
without anemia suggests that the etiologic factors herein considered for the development of
coronary artery anastomoses are not complete
or definitive.
That anemia might stimulate the development of interarterial coronary anastomoses in
otherwise normal hearts might have been anticipated. In 1944, Amadeol"1 suggested that
the infrequency of clinical coronary disease
among the poor rural population of Puerto
Rico resulted from the effect of chronic anemia
upon the development of collateral anastomotic
vessels of the coronary arterial system. In four
hearts from patients with anemia, Scott'39 found
a marked increase in interarterial coronary
anastomoses, as demonstrated by injection of
the coronary arteries with a barium sulfate
suspension in liquid latex."21 In a study of the
coronary arteries by Dock'sll method of perfusion with kerosene, we also found that the
rates of flow were greatly increased in four
hearts from patients with anemia.'40
In the present series the incidence of interarterial coronary anastomoses in "normal human hearts" was reduced from 22 per cent to
9 per cent when the patients with anemia were
eliminated from the group of grossly normal
hearts. In comparison with this low figure, the
incidence of anastomoses in other groups of
hearts assumed statistical significance.
809
Insight into the basic mechanism stimulating
intercoronary anastomoses is afforded by the
demonstration of the roles of anemia and of cor
pulmonale. Relative reduction in oxygen supply to the heart (anoxia) is obviously common
to these two conditions. Anoxia is associated
also with all the other factors related to increased anastomoses. Accumulation of metabolites, lack of substances other than oxygen or
mechanical factors such as differential pressure
gradients in different parts of the coronary system consequent to anoxia, may be other mechanisms that are effective in stimulating anastomoses.
The precise site at which the anoxia is the
critical stimulus for the development of anastomoses is also a matter of speculation. It may
be in the coronary vessels themselves. The
relative insufficiency of oxygen results either
from reduced blood flow in the presence of coronary artery narrowing and occlusion or from
increased demand for blood by the myocardium
in cardiac hypertrophy and valvular disease.
In anemia and cor pulmonale there may be no
reduction in the relative volume of blood flow
through the coronary arteries, but there is a
reduction in the oxygen content of the blood,
resulting from diminished hemoglobin and oxygen capacity in anemia and from diminished
oxygen saturation in cor pulmonale.
Intercoronary arterial anastomoses have
been found in some instances without myocardial histopathologic changes. Cardiac anoxia of
various origins may thus stimulate interarterial
coronary anastomoses without necessarily progressing to the stage of irreversible tissue damage. The reverse observations of hearts with
myocardial damage but without anastomoses
were also made in all categories. Many conditions may thus damage heart muscle irreversibly without necessarily stimulating the development of anastomoses. Nevertheless, in the
control group of hearts with no intrinsic gross
pathology, myocardial damage was infrequent
in comparison with the histopathology found
in hearts with hypertrophy, valvular disease
and coronary artery disease. These normal microscopic findings add validity to the criteria
that were used for the selection of the "normal,
control group."
810
INTERARTERIAL CORONARY ANASTOMOSES IN HUMAN HEART
In this control group there were positive
correlations between myocardial damage, anemia and anastomosis. Deleterious effects of
anemia on heart muscle have been reported by
others."4' Our observations indicate that anemia per se may or may not produce some myocardial damage and that this potentiality is
intimately related to its capacity to stimulate
anastomoses.
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Anemia differs from most of the other conditions associated with the development of intercoronary anastomoses in that it may be
transient and can be voluntarily produced and
controlled in man and in laboratory animals.
Any desired level of anemia may be reached
and maintained by repeated venesections at
appropriate intervals. Furthermore, a critical
degree of anemia may be found which will
stimulate the development of anastomoses and
yet will not result in significant myocardial lesions. Anemia might therefore be used as a
readily controllable investigative tool in studies
pertaining to intercoronary arterial anastomoses.
The data available in the present study do
not indicate clearly the duration and severity
of the anemia that is necessary to stimulate
anastomoses. Anemia of less than six days' duration appears to be without such effect and
marked degrees of anemia seem no more effective than moderate anemia. The question also
remains unanswered whether the newly developed interarterial coronary anastomoses are
permanent or whether they disappear if the
stimulus provoking them is withdrawn. Amadeol'38 came to similar conclusions about the
degree of aniemia. He also assumed that initercoronary aniastomoses produced during the period of ineoniatal aniemia persist throughout life.
Anemia may conceivably have some therapeutic application in the treatment of coronary
artery disease. The presence of anemia for six
months before death in five of the seven patients whose heart muscle w as entirely normal
histologically despite old complete coronary
artery occlusions suggests that pre-existing
anastomoses produced by the anemia may have
helped protect the muscle completely against
the effects of the severe coronary artery disease.
The old occlusions in these patients did not
produce clinical manifestations, however, so
that their temporal relation with the anemia
could not be determined. It would theoretically
be desirable to produce intercoronary anastomoses before the onset of coronary artery narrowing or occlusion; coronary atherosclerosis
would be much less disastrous if the coronary
arteries were not originally functional endarteries. The possibly favorable effects of anemia on the coronary circulation in experimental
animals are now under investigation in this
laboratory.
It is a plausible assumption that the condition (anoxia) which stimulates the formation
of coronary artery anastomoses also produces
the microscopic myocar(lial abnormalities that
are frequently found in the same hearts. On
this basis, in terarterial corol1ary aiiastomosis
may also be regarde(l as an organic abnormality, especially since it is so infrequent in normal
hearts. The functional and organic abnormalities of anemia, chronic pulmonary disease,
cardiac hypertrophy, valv ular heart disease and
coronary artery disease then may be regarded
as etiologic factors in the genesis of physiologic
states of relative myocardial anoxia, and
thereby, of the two anatomic abnormalities of
anastomoses and myocardial histopathology.
The latter two abnormalities tend to appear
together inl the same heart but are not necessarily directly interrelated. The development
of the organic abiiormality of coronary artery
anastomosis is a compensatory response to
these etiologic conditions. In some instances
it is sufficiently protective to forestall or diminish the development of the less desirable
organic abnormality of myocardial damage.
These assumptions are supported by our data
not only inl the large group with coronary artery
disease where they might be considered axiomatic, but in every category discussed above.
CONCLUSIONS
In a series of 1050 human hearts studied by
a method of injection plus dissection of the
coronary arteries, increased initerarterial coronary anastomoses were found in coronary heart
disease, cor pulmonale, antemortem aniemia,
cardiac hypertrophy andlvalvular heart disease.
In 101 grossly normal hearts from nonanemic
P. MI. ZOLL, S. WE1SSLER AND Ml. J. SCHLESINGER
patients the incidence of interarterial coronary
anastomoses was 9 per cent.
In 89 grossly normal hearts from anemic patients the incidence of anastomoses was 39 per
cent.
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In the remaining abnormal hearts the incidenice of interarterial coronary anastomoses was
89 to 100 per cent with coronary artery occlusion, 11 to 63 per cent with coronary artery
narrowing, 73 per cent with COr pulmonale, 26
per cent with cardiac hypertrophy and 28 per
cent with valvular disease.
The factor of relative cardiac anoxia that is
present in all these conditions appears to be a
common underlying stimulus for the development of interarterial coronary anastomoses.
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Interarterial Coronary Anastomoses in the Human Heart, with Particular Reference to
Anemia and Relative Cardiac Anoxia
PAUL M. ZOLL, STANFORD WESSLER and MONROE J. SCHLESINGER
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Circulation. 1951;4:797-815
doi: 10.1161/01.CIR.4.6.797
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