The Inheritance of Coronary Artery
Anatomic Patterns in Rats
By COLIN M. BLOOR, CAPT., MC, ARTHUR S. LEON, MAJOR, MC,
AND
BERTRAM PITT, M.D.
SUMMARY
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Coronary artery anatomic patterns were determined in 4,500 rats obtained from
three unrelated inbred strains. Four basic patterns were defined based on the presence
of one or two primary trunks arising from separate ostia on each side. The frequency distribution of these patterns was significantly different among the three strains. Breeding
experiments showed that the patterns are polygenetically determined. Although the
presence of asymmetrical patterns in each strain suggests independent determination
of each side, some interaction between the factors determining the two sides was also
demonstrated. These patterns may provide a model to test the hypothesis that such
inherited differences in coronary patterns may be a factor in susceptibility or resistance
to coronary atherogenesis and myocardial infarction.
Additional Indexing Words:
Genetics
Heart
Coronary disease
milial similarities in coronary anatomy has appeared. In an autopsy study comparing South
African Bantu and European hearts, Pepler
and Meyer9 stated that a third primary division of the left coronary artery was found
more frequently (P < 0.001) in the Bantu
(74%) than in the European hearts (38%). In an
angiographic study, Sidd and associates'0
found that four brothers, two of whom were
monozygotic twins, had similar coronary artery configurations. In order to explore further the question of inheritance of coronary
artery patterns and their possible relationship
to coronary artery disease, studies were undertaken in this laboratory using the albino
IT has been postulated that variations in the
anatomy of the coronary arterial tree are
likely to have a genetic basis and thus may
be an expression of one of the hereditary
factors in coronary artery disease.2A Indirect
evidence for a genetic basis of coronary artery
pattern variations was provided by Schlesinger's demonstration5 of three principal coronary artery patterns in man, the frequencies
of which were later confirmed by Pitt and associates.6 The finding in various animal species of different dominant patterns of coronary branching7 and anastomoses8 also points
to a genetic basis.
Recently, direct evidence of racial and fa-
rat.
Methods
The 4,500 rats used in this study were randomly obtained from unrelated, isolated, inbred
populations maintained at the Walter Reed Army
Medical Center (WR), the National Naval Medical Center (NNMC), and the National Institutes
of Health (NIH). The WR strain was started
from the CF Nelson strain in 1955 and has been
perpetuated by random matings, while the NNMC
strain originating from Sprague-Dawley rats in
From the Department of Cardiorespiratory Diseases, Walter Reed Army Institute of Research, Walter
Reed Army Medical Center, Washington, District
of Columbia.
Preliminary reports of part of this work were
presented at the Annual Meeting of the American
Society for Experimental Pathology,' Atlantic City,
New Jersey, April 11 to 16, 1966, and at the New
York Academy of Sciences Symposium on Recent
Advances in Atherosclerosis, New York, New York,
November 21 to 23, 1966.
Circulation, Volume XXXVI, Novrember 1967
771
BLOOR ET AL.
772
1963 and the NIH strain originating from Heston's Buffalo strain in 1950 have been perpetuated by brother-sister matings. No common ancestry is known to exist between the tliree strains.
Following sacrifice of the animals with ethier,
the hearts were removed, and the anatomic patterns of the coronary arteries were demonstrated
either by gross dissection or Vinylite plastic casts.
Dissection of the lhearts was condticted under a
dissecting microscope to expose the aortic sin-uses
of Valsalva and coronary ostia. The number of
primary coronary trunks arisinig from independent
ostia was tlhen- determinecd, and their couirses
were followed by ftirther gross dissectioni. In
randomly selected animals, Viinylite casts of the
coronary arteries were prepared according to the
method of Tepperman and Pearlman." The major coronary artery patternis observed in the three
strains are demonstrated irn figure 1.
The frequency of these patterns was determined in 1,469 randomly selected male and
female rats from the three strainls. The mode of
inheritance was defined by using controlled
breeding. The XVR and NNMC strains wer e crossed
to prodince F, anld F2 generations, and their
coronary artery patterns were subsequently determined. In aniother breedling program, the influence of parental backgrounid on coronary
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Figure 1
Foutr coroniary artery patterns, based on the n2umber of primary trunks arising from the aorta
on eacch side, as sce'n in the Vinylite plastic cast (A) and the opened aorta (B, C, and D). (A)
Type 1/1 comprises a single main trunk arising from a single ostiu4m onr botih the left (L) anid
right (R) sides. (B) Type 2/1 consists of two main trunks arising from separate ostia on the
left side (L) teith a sinigle mairt trunk arising from a single ostium oni the right (R). (C) Type
1/2 has a sinigle mait trutnik arising front a single ostium on the left side (L) with two mcain
trunks arisinrg fronti separate ostia on the right side (R). (D) Type 2/2 coniprises twto main
tnnks arising from separate ostia otn both the left (L) and right sides (R).
Circolation, Volume XXXVI, November 1967
INHERITANCE OF CORONARY PATTERNS
100
W NNMC NIH
773
Table 1
Frequency of Single and Double Coronary
Arteries on Each Side
Frequency of single and double coronary arteries (%)
Right
Left
Double
Single
Double
Single
80
Strain
WR
NNMC
NIH
60
Frequency
(M)
40
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20
fL
1/1
2/1
1/2
Coronary Artery
2/2
Patterns
Figure 2
Frequency of the four major coronary artery patterns
illustrated in figure 1, in the WR, NNMC, and NIH
strains.
artery variation was studied by randomly mating
WR rats and comparing the coronary patterns
of the offspring with those of their parents.
Results
A significant difference (P <0.001) in the
frequency distribution of the four coronary
artery patterns was present among the three
unrelated strains (fig. 2). In the NIH strain,
the frequencies of two patterns (type 1i/
and type 1/2) resembled those of the WR
strain, while the frequencies of the other two
patterns (2/1 and 2/2) were similar to those
of the NNMC strain. The presence of these
differences between inbred strains is evidence
that genetics plays a role in the determination
of coronary artery patterns. The frequencies
of these coronary patterns within each strain
were similar for both sexes (P > 0.4) showing
that the inheritance is not sex-linked.
Asymmetrical patterns (2/1 and 1/2, fig.
1) are present in each strain (fig. 2) suggestCirculation, Volume XXXVI, November 1967
21.6
7.3
24.2
78.4
92.7
75.8
11.5
1.7
1.7
88.5
98.3
98.3
ing independent determination of each side.
In table 1, the frequencies of single and
double coronary trunks are listed for each
side separately.
Detailed dissection of 250 WR rats revealed
that, in hearts with two primary left coronary
trunks, the second trunk was usually (67%) a
septal artery arising independently from the
aorta while the remaining hearts (33%) had
anterior descending and left circumflex coronary arteries arising separately. On the right
side, the second trunk was predominantly
(75%) an independent septal artery and in
the others it usually was a conus artery arising
separately from the aorta.
Seventy pairs of WR and NNMC rats were
cross-mated to produce F1 and F2 generations. The frequencies of the coronary patterns on each side in the parental F1 and F2
generations are displayed in figure 3. The frequencies of the two patterns on the right side
CORONARY ARTERY PATTERNS
LEFT
Generation
WR
l
Fl
r
RIGHT
LI
_7
I.
F2
Fl
NNMC
O
20
40
60
so
1010
O
20
40
60
S0
Percent Distribution
Figure 3
Per cent distribution of single (white) and double
(stippled) coronary arteries on each side in the
parenteral (WR and NNMC) FJ hybrid and F2
generations.
774
BLOOR ET AL.
strain. The frequency of coronary artery patterns in the offspring are listed for each side
according to the parental mating (table 2).
When both parents had a similar coronary pattern on one side, a higher frequency of that
pattern was found in the progeny than when
neither parent had it. Intermediate frequencies resulted when only one of the parents
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are seen in the F1 generation to be intermediate to those observed in the parental strains.
In the F2 generation, the frequencies of the
right side patterns are similar to those of the
WR strain, suggesting that the WR strain has
the dominant influence in determining the
right coronary artery pattern. On the left side,
the facts that the F1 generation frequencies
are similar to those observed in the NNMC
strain and that intermediate frequencies only
appear in the F2 generation suggest that the
NNMC strain is dominant with respect to
the left coronary pattern. The fact that the
frequency changes of the patterns on the two
sides in the F1 and F2 generations are not
parallel further demonstrates the existence of
independent factors in their determination.
Coronary artery patterns were determined
in 3,300 newborn rats and their parents from
351 randomly obtained litters from the WR
had the particular pattern.
In table 3, the data obtained from the newborn rats and their parents have been re-arranged to determine whether the presence
of a single or double coronary artery pattern
on one side influences the frequency of the
corresponding pattern on the opposite side in
the offspring. The presence of a single or
double left coronary pattern in the parents
fails to increase the frequency of the corresponding pattern on the right side in the
offspring. However, when rats with the same
Table 2
Frequency of Coronary Artery Patterns of the Same Side in Offspring and Parents
Grouped According to Parental Patterns
4
Parental patterns
No.
of
matings
Frequency of single and double coronary
arteries of the sam,ze side in offspring
(%)
Single
Double
No.
of
offspring
Left 1 X 1
1x2
2x2
270
72
9
2573
654
74
Right
104
162
85
1017
1495
789
x2 =
91.6
87.6
86.5
x2=- 11.43
1 x 1
1X2
2x2
56.85
8.4
12.4
13.5
P<0.01
74.6
71.2
58.8
P < 0.001
25.4
28.8
41.2
Table 3
Frequency of Coronary Artery Patterns of the Opposite Side in Offspring Grouped
According to Parental Patterns
Parental patterns
Left 1 X 1
1x2
2X2
Right 1 x 1
1x2
2X2
No.
of
matings
270
72
9
104
162
85
No.
of
offspring
2573
654
74
x2= 0.49
1017
1495
789
2 = 10.29
Frequency of single and double coronary
artqries of the opposite side in offspring
(%)
Single
Double
69.6
68.2
70.3
P>0.7
92.2
91.2
88.0
P < 0.01
30.4
31.8
29.7
7.8
8.8
12.0
Circulation, Volume XXXVI, November 1967
INHERITANCE OF CORONARY PATTERNS
right coronary artery pattems were mated,
the offspring had an increased incidence of
that particular pattern on the left side, showing that the factors determining the right
coronary artery patterns also had partial influence on the determination of the left coronary artery pattern.
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Discussion
Coronary artery anatomic patterns in rats
exhibited variation within inbred strains with
the dominant phenotypic type comprising
single primary trunks on the right and left
sides. The presence of significant differences
in the frequency distribution of the various
patterns among the inbred strains is evidence
that genetics plays a role in the determination of coronary artery patterns. The observed
frequencies of the coronary patterns in the
breeding experiments differ from those expected if classical mendelian segregation involving single pairs of genes exhibiting dominance and recessiveness were involved. All
of these findings indicate that polygenetic determination is the most likely mode of inheritance. This type of inheritance is characterized by the interaction of many pairs of
genes, each having a small effect on the development or modification of a trait.
In polygenetic inheritance of anatomic characters, environmental factors, that is, external
and internal phenomena affecting the internal
milieu during critical periods of development,
also play an important role. The role of environmental factors in the determination of
coronary artery patterns is illustrated in our
data by the variability of patterns within inbred strains. Quantitative genetic methods
are needed to define further the relative importance of genetic and environmental factors
in coronary artery inheritance.
The independent variation of vascular
structures, including aortic branches, on the
two sides of the body has been reported.'12 13
Similar phenomena have also been observed
with skeletal structures.'4 The presence of
asymmetrical patterns in each of our inbred strains suggests that coronary artery patterns on the right and left side are also inCirculation, Volume XXXVI, Novem;ber 1967
775
dependently determined. The evidence from
the F, and F2 generations showing that the
WR strain has the major influence on the right
coronary pattern while the NNMC exerts the
major influence on the left coronary pattern
further substantiates this view. Although coronary artery pattern determination appears
to be basically independent, it is of interest
that within the WR strain there is some interaction between factors determining the two
sides as evidenced by the influence of the
right coronary parental pattern on the left
coronary pattern in the offspring (table 3).
The demonstration in this study that genetic
factors play a role in determining the configuration of the coronary arterial tree adds support to recent reports of racial and familial
similarities of coronary anatomy in man.9' 10
Such inherited variations in coronary artery
patterns are thought to be one of the important hereditary factors in determining susceptibility or resistance to coronary atherosclerosis and myocardial infarction. The presence of
an additional primary coronary artery or main
branch may serve as a potential source of
collateral circulation upon occlusion of a main
coronary artery. The low incidence of myocardial infarction in the Bantu,9' 15 may be on
this basis. It has also been shown that anatomic variations may create hemodynamic
conditions which favor the development of
thromboses and atheroma.'F'8 By subjecting animals with various coronary artery
patterns to atherogenic stimuli, it should be
possible to determine the relationship between the ensuing pathological changes and
the particular anatomic pattern.
References
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Circulation, Volume XXXVI, November 1967
The Inheritance of Coronary Artery Anatomic Patterns in Rats
COLIN M. BLOOR, CAPT., ARTHUR S. LEON, MAJOR and BERTRAM PITT
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Circulation. 1967;36:771-776
doi: 10.1161/01.CIR.36.5.771
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