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cushions in the developing mouse heart. 1 The atrioven-
tricular (mitral and tricuspid) valves have the highest
levels of type I collagens in the heart. 1 A strain of mice
( oim ) with a spontaneous single nucleotide deletion
(c.3983delG) mutation in Col1a2 mimics several pheno-
typic features of OI. 4 A recent manuscript reports com-
prehensive analysis of the cardiac valves in these mice. 5
Homozygous oim mice have marked thickening of the
leaflet tips of the aortic valves, with increased proteogly-
can deposition, characterized by pentachrome staining.
The most severely affected portion was the distal leaf-
let tips, which were 157 ± 31 μM compared to 77 ± 4 μM
in the heterozygous oim mice; P ≤0.05. In contrast, the
mitral valve leaflets were not significantly different in
oim / oim mice vs. heterozygous controls. 5
Taken together, the murine and human studies indi-
cate the potential for any person with any type of OI to
develop cardiac valve disease. Developmental and adult
mouse data document the role of type I collagens in the
heart, and the response to its deficiency. Human studies,
although relatively small, confirm valvular insufficiency
in this population. Larger population-based investigations
will likely confirm and extend these findings, and charac-
terize the burden of cardiac valve regurgitation in OI.
critical role for type I collagen in arterial vascular devel-
opment. 8,9 Subsequent targeting of the first intron of
Col1a1 led to reduction of its expression with viability. 10
Rahkonen and colleagues analyzed this strain of mice
with hypomorphic expression of Col1a1 , demonstrating
aortic dissections in homozygous mice, associated with
elastic lamellae that were less compacted and more vari-
able in width, with irregular borders and less surround-
ing collagen. 11
Premature calcification, stenosis and dissection of
medium-sized arteries, such as coronary or cerebral
vessels, in people with OI have been described in case
reports and textbooks. 12-14 However, arterial steno-
sis does not typically cause symptoms or impair distal
perfusion until at least 70% occluded. Comprehensive
evaluation of cohorts with OI for these findings would
be challenging, so the true incidence of medium-sized
vascular stenosis in OI is not known. The absence of
reported vascular atherosclerosis/calcification in mice
with mutations in Col1a1 or Col1a2 may simply reflect the
difficulties of causing this problem in mice within their
short lifespan. 15
Aortic size should be considered in the context of
body size, particularly in growing children. 16 Among
individuals with severe (type III) OI, BSA is typically
much lower than age-matched controls. Figure 34.1
shows the ranges of aortic root dimensions in children
and adults, normalized for body size and age. These
ranges were obtained from echocardiographic study of
135 normal adults and 52 normal children, and they are
commonly used for disorders like Marfan syndrome
in which BSA may be skewed in the opposite direction
from OI. 16,17
ARTERIAL DISEASE
Within the vasculature, both type I and type III col-
lagens play an important role. Mutation in COL3A1
encoding type III collagen results in vascular Ehlers-
Danlos syndrome (vEDS), a disorder characterized by
aneurysms and dissections of the large and medium-
sized vasculature. Type III collagen forms the majority
of collagen in the medial layer of the aorta, while type
I collagens are the major form of collagen in the aortic
adventitia. 6,7 Accordingly, problems with the arterial
vasculature are not surprising in OI. The early M-mode
echocardiographic analysis of 66 probands with OI
found aortic root dilation (>127% of age- and weight-
predicted dimension) among 12.1%. 2 Although
Migliaccio reported no significant difference in aortic
root size among a cohort of 40 people with OI compared
to controls (22.7 vs. 22.0 mm, respectively), the Norway
survey found a mild increase in aortic root size in OI vs.
controls (29.5 vs. 28.6 mm, respectively); this was not sig-
nificant.48 48 Aortic root and ascending aortic size are typi-
cally normalized to body surface area (BSA), which is
often reduced in OI, particularly the more severe types III
and IV. When normalized to BSA, the difference in aortic
root dimension in the Norway OI study was clear (18.6
vs. 15.4 mm/m 2 , respectively, P ≤0.05).
Retroviral integration into the first intron of Col1a1
causes loss of its expression, with embryonic lethality
(ED 12-14) due to arterial rupture, thus establishing a
MYOCARDIAL DISEASE
In addition to heart valves and arteries, type I col-
lagen is also present in the ventricular myocardium.
Together with type III collagen, it forms a fibrillar net-
work that appears to function as a scaffold for cardio-
myocytes in the ventricles. 18 In response to most forms
of myocardial injury, collagen synthesis is increased,
which contributes to cardiac hypertrophy and fibro-
sis. Cardiovascular evaluations in people with OI have
mostly focused on heart valves and vasculature, but the
Norwegian adult OI survey also included analysis of left
ventricular (LV) mass and wall thickness. 3 Among the
cohort of 99 affected individuals, the average LV septal
wall thickness was within the normal range, but greater
than controls (1.01 ± 0.28 vs. 0.87 ± 0.15 cm respectively;
P <0.05. 3 After normalization for BSA, which was lower
in OI than among controls, the difference was aug-
mented. Similarly, LV mass was greater in OI than in
controls (158 ± 53 vs. 138 ± 44 g respectively; P <0.05);
 
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