Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan?
OBJECTIVE
Marfan syndrome is a systemic connective tissue disorder caused by mutations in the fibrillin-1 gene. It was originally believed that Marfan syndrome results exclusively from the production of abnormal fibrillin-1 that leads to structurally weaker connective tissue when incorporated into the extracellular matrix. This effect seemed to explain many of the clinical features of Marfan syndrome, including aortic root dilatation and acute aortic dissection, which represent the main causes of morbidity and mortality in Marfan syndrome.


METHODS
Recent molecular studies, most based on genetically defined mouse models of Marfan syndrome, have challenged this paradigm. These studies established the critical contribution of fibrillin-1 haploinsufficiency and dysregulated transforming growth factor-beta signaling to disease progression.


RESULTS
It seems that many manifestations of Marfan syndrome are less related to a primary structural deficiency of the tissues than to altered morphogenetic and homeostatic programs that are induced by altered transforming growth factor-beta signaling. Most important, transforming growth factor-beta antagonism, through transforming growth factor-beta neutralizing antibodies or losartan (an angiotensin II type 1 receptor antagonist), has been shown to prevent and possibly reverse aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction in a mouse model of Marfan syndrome.


CONCLUSIONS
There are indicators that losartan, a drug widely used to treat arterial hypertension in humans, offers the first potential for primary prevention of clinical manifestations in Marfan syndrome.
Matt
Peter
P
Howard Hughes Medical Institute and Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. pmatt@uhbs.ch
Habashi
Jennifer
J
Carrel
Thierry
T
Cameron
Duke E
DE
Van Eyk
Jennifer E
JE
Dietz
Harry C
HC
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000188:drug therapy* / Q000517:prevention & control* / Q000601:surgery; D015331:Cohort Studies; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D005819:Genetic Markers; D006801:Humans; D019808:Losartan / Q000627:therapeutic use*; D008382:Marfan Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D018570:Risk Assessment; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D005819:Genetic Markers; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; D019808:Losartan