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In Depth Tutorials and Information
PATHOPHYSIOLOGY OF
CAR
DIOVASCULAR DISEASE I
N OI
TGFβ ligand was not significantly different from con-
trols.
34
Taken together, these findings support a potential
role for increased TGFβ activity in the pathogenesis of
OI-related cardiovascular disease.
The most obvious potential mechanism for the car-
diovascular manifestations of OI relies on a structural
deficiency mediated by the loss of type I collagen in tis-
sues where it is normally abundant. For instance, aortic
enlargement or cardiac valve insufficiency could simply
be due to collagen deficiency in the extracellular matrix,
with consequent tissue fragility. With hemodynamic
stress, the collagen-deficient heart, cardiac valves and
arterial vasculature would inevitably be predisposed to
mechanical failure. With this model of disease pathogen-
esis, treatment options would be limited to those that can
reinforce or substitute for the inherent structural deficit.
If this were the principal cause, then the incidence and
severity of cardiovascular manifestations should directly
correlate with the severity of skeletal disease, with much
more frequent and severe cardiac and vascular findings
in people with type III than with type I OI. Because this
is not true, other factors likely play an important role in
cardiovascular disease pathogenesis.
Cardiac valve insufficiency and aortic enlargement are
much more commonly seen in another connective tissue
disorder, Marfan syndrome.
17
Despite the initial suspi-
cion for the same type of structural deficiency mediated
by the deficiency of fibrillin-1 in people with this condi-
tion, extensive investigation has identified a regulatory
role for this extracellular matrix protein wherein its defi-
ciency causes increased activation and signaling of trans-
forming growth factor-β (TGFβ).
27-29
Fibrillin-1 shares
homology with the latent TGFβ-binding proteins, which
help to stabilize the large latent complex of this growth
factor. Indeed, LTBPs have been demonstrated to bind
directly to fibrillin-1 and to participate in modulation of
TGFβ by the extracellular matrix.
30,31
Although direct assessment of TGFβ activity has not
been reported in OI-related cardiovascular disease, sev-
eral lines of evidence support a possible role for this
growth factor in its pathogenesis. TGFβ has been shown
to have a regulatory role in collagen production, increas-
ing the production of both types I and III collagens in
the heart.
32
In addition, the amino-terminal propeptide
of type I procollagen interacts with TGFβ1, and overex-
pression of the N-propeptide also increases the phos-
phorylation of Smad3, a downstream mediator of TGFβ
activation.
33
Finally, citing discordance between geno-
types and phenotypic manifestations in OI, Gebkin and
colleagues investigated the cell surface expression and
functional properties of the TGFβ receptors (types I, II
and III) in osteoblasts from a cohort of people with OI
compared to unaffected controls.
34
They showed that
OI-associated osteoblasts had a 2.4-fold higher num-
ber of TGFβ receptors per cell, and that their affinity for
MEDICAL TREATMENT
As previously noted, there are several cardiovascular
complications that may accompany OI. These include
regurgitation or insufficiency of the cardiac valves,
aneurysm or dissection of the aorta and ventricular dys-
function occurring as a primary disorder or secondarily
manifesting because of increased susceptibility to myo-
cardial injury. Although there are no large clinical trials
testing medications for these conditions in OI, one can
infer the feasibility of medical therapies from larger pop-
ulations with these cardiovascular conditions. For most
forms of valve insufficiency, afterload reduction with
vasodilators should favorably alter the hemodynam-
ics to improve the effective cardiac output. In particular,
angiotensin-converting-enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs) have been tested
for their benefits in mitral regurgitation, and a recent
meta-analysis supports their use.
35
But the benefits for
these medications are modest, and surgical therapy is
preferable for more severe disease, if possible.
Several studies investigating the pathogenesis of aor-
tic aneurysms in Marfan syndrome and related forms of
familial aortic aneurysm have highlighted the role of TGFβ
in their pathogenesis. Because of interactions between
TGFβ and angiotensin II signaling, studies investigat-
ing angiotensin receptor blockers show great promise for
medical treatment of these aortic diseases. However, the
role of TGFβ in OI-related aortic disease is not yet estab-
lished. Indeed, because TGFβ stimulates expression of sev-
eral forms of collagen, therapies that reduce the signaling
of this growth factor could modulate beneficial compensa-
tory responses to type I collagen disorders. Until there is
more evidence supporting the use of angiotensin receptor
blockers for OI, treatment with beta-blockers appears to be
safer. For any patient with aortic enlargement (>2SD pre-
dicted for age and BSA), yearly follow-up imaging with
echocardiography/ultrasound, magnetic resonance imag-
ing or computed tomography should be performed.
Prevention or treatment of right ventricular failure
should be directed at the underlying pulmonary hyper-
tension that can occur in individuals with OI-related
lung disease. There are several strategies to address
pulmonary hypertension, but no studies directly assess
the relative efficacy and safety in OI. Inhibition of phos-
phodiesterase type 5 can be achieved with sildenafil or
tadalafil, and these medications are FDA approved for
the treatment of pulmonary hypertension in adults.
36
