Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations.
BACKGROUND
The major clinical problem of Marfan syndrome (MFS) is the aortic root aneurysm, with risk of dissection when the root diameter approximates 5 cm. In MFS, a key molecule, transforming growth factor-beta (TGF-beta), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-beta blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-beta effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. beta-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation beta-adrenergic blocker nebivolol retains the beta-adrenergic blocker effects on heart rate and further exerts antistiffness effects, typically increased in MFS.


METHODS
The open-label phase III study will include 291 patients with MFS and proven FBN1 gene mutations, with aortic root dilation (z-score > or =2.5). The patients will be randomized to nebivolol, losartan and the combination of the two drugs. The primary end point is the comparative evaluation of the effects of losartan, nebivolol and the association of both on the progression of aortic root growth rate. Secondary end points include the pharmacokinetics of the two drugs, comparative evaluation of serum levels of total and active TGF-beta, quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3'), pharmacogenetic bases of drug responsiveness. The quality of life evaluation in the three groups will be assessed. Statistical evaluation includes an interim analysis at month 24 and conclusive analyses at month 48.


CONCLUSIONS
The present study will add information about pharmacological therapy in MFS, supporting the new application of angiotensin receptor 1 blockers and finding beta-adrenergic blockers that may give more specific effects. Moreover, the study will further deepen understanding of the pathogenetic mechanisms that are active in Marfan syndrome through the pharmacogenomic and transcriptomic mechanisms that may explain MFS phenotype variability.
Centre for Inherited Cardiovascular Diseases, Italy.
Fabiana I
FI
Gambarin
Valentina
V
Favalli
Alessandra
A
Serio
Mario
M
Regazzi
Michele
M
Pasotti
Catherine
C
Klersy
Roberto
R
Dore
Savina
S
Mannarino
Mario
M
Viganò
Attilio
A
Odero
Simona
S
Amato
Luigi
L
Tavazzi
Eloisa
E
Arbustini
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001014:Aortic Aneurysm / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001578:Benzopyrans / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004108:Dilatation, Pathologic; D018450:Disease Progression; D004983:Ethanolamines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007223:Infant; D019808:Losartan / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008382:Marfan Syndrome / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D000068577:Nebivolol; D011788:Quality of Life; D012107:Research Design; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000097:blood; D016896:Treatment Outcome; D055815:Young Adult; D054392:Adipokines
D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D001578:Benzopyrans; D004983:Ethanolamines; D000071838:Fibrillin-1; D000071837:Fibrillins; D019808:Losartan; D008840:Microfilament Proteins; D000068577:Nebivolol; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines