Acute Aortic Disease.. - Index of

Genetic Basis of Thoracic Aortic Aneurysms 123
dissections have TGFBR1/2 mutational analysis to screen for mutations in these
genes as a cause of disease because finding such a mutation has significant implications
for the subsequent management of the patient and their family. We hope
that in the future, more genes will be identified that can be screened for mutations
in families with thoracic aortic aneurysms and dissections.
Do you think that the ARB drugs will prove to be a panacea for aneurysm disease?
Does this possibility seem almost too good to be true?
It will be determined if the success of losartan in blocking the progressive aortic
disease in a mouse model of MFS will also apply to humans with MFS, in a clinical
trial comparing beta adrenergic blocking agents to losartan. The clinical trial,
funded by NHLBI and using the Pediatric Heart Network, will recruit patients
under the age of 26 years with MFS and randomize them to either drug. A similar
trial of adults with MFS is in the planning stage.
It is not certain if the success of losartan in the animal model of MFS will
translate to humans with MFS. In addition, we do not know the role of TGF beta signaling
in aortic disease in patients who do not have MFS. Further studies are needed
to determine if ARB drugs will prove to be a panacea for aneurysm disease.
References
1. Glesby MJ, Pyeritz RE. Association of mitral valve prolapse and systemic abnormalities
of connective tissue. A phenotypic continuum. JAMA 1989; 262:523–528.
2. Dietz HC, McIntosh I, Sakai LY, et al. Four novel FBN1 mutations: significance for
mutant transcript level and EGF-like domain calcium binding in the pathogenesis of
Marfan syndrome. Genomics 1993; 17:468–475.
Editor’s Comments
Dr. Milewicz et al. have made extraordinary contributions to the fundamental
genetic understanding of aortic diseases, which they enumerate clearly in this
chapter. Their work reflects tremendous industry, acumen, and insight. The entire
vascular community respects and is grateful for it.
Our own team is working with molecular geneticists at Celera Diagnostics in
California to explore the automated SNP avenue of investigation that Dr. Milewicz
describes. Our preliminary findings have shown that (1) aneurysm disease has a
unique “RNA signature” in the peripheral blood. (2) This signature, if confirmed
in further investigations, promises to facilitate clinical diagnosis of aneurysm disease
on a molecular genetic basis. Our separate investigations on 30,000 DNA SNPs
is ongoing. We hope to identify specific alterations in the genome of aneurysm
patients. The DNA studies look at the blueprint which programs the body is to be
made. The RNA studies look at which proteins are actually upregulated or
downregulated in terms of active manufacture at the time of sampling.
In terms of clinical genetic patterns, our most recent examination of
520 family pedigrees of patients with thoracic aortic aneurysms indicates that there
are distinct patterns of inheritance among family members. (3) Family members