A presentation about ARB use in Marfan syndrome patients

1. ANGIOTENSIN-RECEPTOR
BLOCKERS USED IN THE
TREATMENT OF
MARFAN’S SYNDROME
By: Tomas C. Pitts
MSIII

2. What is Marfan’s Again?
 Marfan’s syndrome is a disorder of
the body's connective tissue that
can affect the skeletal system,
blood vessels, heart, lungs, eyes
and other organ systems.

3. Who gets Marfan’s and how?
 Marfan syndrome can be inherited from either
parent, or it can result from a new change in
genetic material. If a parent has Marfan
syndrome, offspring have a 50-50 chance of
inheriting the disorder. Approximately 200,000
people in the United States have Marfan
syndrome, which can occur in men or women of
any race or ethnic group. Many affected
individuals are young adults, adolescents or
children.

4. Clinical Signs

5. Common Complications of
Marfan’s Syndrome.
 Aortic Insufficiency – Diastolic decrescendo
murmur @ the upper L. sternal border.
(Aortic dilation, Aortic regurgitation, Aortic
aneurysm).
 Aortic dissection – Tearing pain radiating to
the back, asymmetrical upper ext. pulses.
 Mitral Valve Prolapse – Midsystolic “click” w/
late systolic murmur.

6. Traditional Marfan’s Tx.
 Beta Blocker (Atenolol/Propanolol)
 ACE Inhibitor (Lisinopril)
 Calcium Channel Blocker (Verapamil)
 We are now starting to realize the potential of
the ARB’s in Marfan’s Sx. (Ex: Losartan)

7. Trial
 A control group consisted of 65 children with Marfan’s
syndrome who were not treated with an ARB.
 The median age of the patients was 6.5 years, and half of
them were boys. The mean aortic root diameter before
ARB therapy was 3.7 cm, and the median duration of
treatment was 49 months. No changes in heart rate or
blood pressure occurred after initiation of the ARB. The
mean rate of aortic root enlargement before treatment
was 3.54 mm per year; after therapy was started, the
mean rate was 0.46 mm per year (P<0.001). The more
distal sections of the aorta, usually unaffected by Marfan
syndrome, continued to show an age-appropriate growth
rate. In the control patients who received beta-blockers
but not ARBs, the mean rate of change was 1.71 mm per
year.

8. Why Does The ARB Slow
Dilation of the Aortic Root?
 Not entirely sure
 Inhibition of excessive TGF-β signaling (due to
fibrillin-1 mutation) and subsequent inhibiton
of matrix metalloproteases (notably MMP’s 2
& 3).
 This reduces extracellular matrix
deterioration and thus, aortic dilation

9. Matrix Metalloproteinases
 Implicated in tumor invasion
 Remodels insoluble components of basement
membrane.
 Releases ECM-sequestered growth factors.
 Has chemotactic, angiogenic, and growth
promoting effects (ex. MMP9 – cleaves
collagen of epithelial and vascular basement
membrane and stimulates VEGF from ECM
sequestered pools.

10. Matrix Metalloproteinases
cont.
 The body’s stores of metalloproteinase
inhibitors are greatly reduced during these
insults and greatly shifts the balance in favor
of tissue degradation.
 Exogenous MMP inhibitors have had poor
results because the body can switch between
using MMPs and Ameboid migration which
allows cells to use collagen IV as a “highspeed
railway” to navigate the matrix and
attack/invade the target tissue.

11. Transforming Growth Factor β
 Loss of microfibrils give rise to abnormal and
excessive TGF- β.
 Excessive TGF- β has deleterious effects on
vascular smooth muscle development and
the integrity of the extracellular matrix.
 In mice models TGF- β antibodies helps to
prevent this damage and similar human
studies seem to be promising (Robbins,
Pathologic basis of disease, pg. 145)

12. So why the ARB over the ACE
inhibitor?
 Angiotensin II type 1 receptor plays a role in
upregulating TGF-β signaling and thus further aortic
dilation leading to increased risk of dissection.
 Both agents lower blood pressure but the ARB also
inhibits TGF- β signaling to a greater extent (thus
slowing aortic dilation to a greater extent).
 The ARB is not associated with an increase in
bradykinin which cause cough in ACE inhibitor s and
can lead to non-compliance.

13. Teamwork!
 Researchers are entertaining the possibility of
“cross talk” between protective mechanisms
and the possibility of a synergistic protective
effect with ACE inhibitor, β-Blockers, and
ARB’s. Also, because TGF- β can also activate
the non-tyrosine kinase c-abl which can
cause tissue fibrosis and contribute to
Marfanoid pathology. Imatinib is now being
used in mouse models as a potential
treatment in Marfan’s Sx as it inhibits this
mechanism.

14. There is always a Con
 There are over 800 recognized defects of the
fibrilin-1 gene which can effect TGF- β
signaling to different degrees. Some
mutations actually decrease TGF- β signaling
due to mutations in the coding of TGF-β
receptor 2. In these particular mutations, an
ARB may actually have an adverse effect.

15. Exceptional cases
 Marfan’s sx. may be caused by other genetic
defects including at the level of the TGF- β
receptor (TGFBR1 & TGFBR2). The effects
ARBs in these cases is still under
investigation. These types of Marfan’s can be
distinguished clinically because they lack the
distinguishing craniofacial & cutaneous
features as well as an absence of lens
dislocation. In these patients traditional
treatment is indicated.

16. Gracias! Grazie! Thank You!

17. Reference
 Brooke BS et al. Angiotensin II blockade and
aortic-root dilation in Marfan’s syndrome. N
Engl J Med 2008 Jun 26; 358:2787.
 Pathologic basis of disease, Robbins &
Cotran, 2010 Saunders, pg 145