D. F. PATTERSON 
993 
of producing affected offspring was achieved, 
regardless of the mode of inheritance which 
might be operating. The lesions tested were pat- 
ent ductus arteriosus in Poodles, pulmonic sten- 
osis in Beagles, subaortic stenosis in Newfound- 
lands, persistent right aortic arch in German 
Shepherds, and tetralogy of Fallot in Keeshon- 
den. In each instance, hereditary transmission 
of congenital heart disease was demonstrated, 
the incidence of defective offspring reaching as 
high as 90% in some matings.'* '' The cardio- 
vascular defect in the affected offspring was 
usually the same or closely related to that in the 
parents. These findings confirm the hereditary, 
lesion-specific nature of the defects tested, and 
indicate that through selective breeding a high 
incidence of offspring with predictable cardio- 
vascular defects can be produced for a variety of 
research purposes. 
Further genetic studies have shown that al- 
though some of the lesions tested are transmit- 
ted in a manner superficially resembling autoso- 
mal dominant inheritance, none can be ex- 
plained on a simple genetic basis.® '^ The most 
completely analyzed defect is patent ductus ar- 
teriosus. Further discussion of gross anatomic 
defects will be confined to this anomaly. 
HEREDITARY PATENT DUCTUS ARTERIOSUS 
(PDA) IN POODLES 
Defective closure of the ductus arteriosus in 
Poodle dogs is a localized developmental anom- 
aly determined by multiple genetic factors which 
appear to act additively.^ Thus, what appears 
on the surface to be a discontinuous trait ac- 
tually results from a more or less continuous 
underlying distribution of genetic determinants 
which affect the normal ductal closure mecha- 
nism. Discontinuity at the gross phenotypic 
level occurs when their cumulative effects ex- 
ceed some critical threshold and the ductus ar- 
teriosus fails to close. Careful scrutiny of 
offspring from matings of dogs with PDA 
shows that there are not simply two phenotypic 
classes. In addition to normal pups, and those 
with PDA (Figure 1), there is an intermediate 
phenotype in which the lumen of the ductus ar- 
teriosus is obliterated at the pulmonary arterial 
end, while a variable portion of the segment ad- 
joining the aorta remains open. This gives rise 
to a funnel-shaped ductus diverticulum which 
appears as an outpocketing of the ventral (ster- 
nal) wall of the aorta at the site of the ostium 
of the ductus arteriosus (Figure 2, bottom). 
This forme fruste of hereditary PDA is clini- 
cally silent, being detected in living animals 
only through the use of aortic angiography 
(Figure 2, top) . In test matings, dogs with duc- 
tus diverticulum did not differ markedly from 
dogs with fully patent ductus arteriosus in the 
ability to transmit defective ductal closure to 
their offspring.^ 
The results of experimental matings of dogs 
with PDA are consistent with a polygenic model 
having two developmental thresholds.^ The first 
threshold separates complete closure of the duc- 
tus arteriosus from ductus diverticulum, and 
the second separates ductus diverticulum from 
complete patency of the ductus arteriosus. 
These two thresholds may be looked upon as 
two distinguishable points along a continuous 
scale of "liability" to abnormal development 
which extends in both directions. Assuming 
that liability is continuous and normally dis- 
tributed, the mean and standard deviation of 
liability of a group of individuals may be deter- 
mined from the incidence of the three pheno- 
typic classes (normal, ductus diverticulum, 
PDA) by referring to a table of the normal 
curve. ^ Figure 3 shows the distribution of lia- 
bility to defective ductal closure in three groups 
of offspring, each receiving a different propor- 
tion of its genome from dogs with PDA. As the 
PDA-derived portion of the genome (r value in 
Figure 3) increases from V2 to % to 1, the 
mean liability of the offspring is progressively 
shifted to the right, beyond the thresholds for 
ductus diverticulum and PDA. 
Left Heart Failure and Pulmonary Hypertension 
in Pups with Hereditary PDA 
While increasing phenotypic severity beyond 
the threshold for PDA is not considered in the 
model shown in Figure 3, other evidence sug- 
gests that with an increasing "dose" of genes 
predisposing to abnormal ductal closure, there 
is a continuing increase in the severity as well 
as the incidence of the underlying lesion. The 
