Pediatric Heart Network Trial of Losartan vs. Atenolol in Children and Young Adults with Marfan Syndrome: Impact on Prescription Practices

Robertson, Dwight M; Truong, Dongngan T.; Cox, Daniel A.; Carmichael, Harris; Ou, Zhining; Minich, L. LuAnn; Williams, Richard V.; Tierney, Elif Seda Selamet

doi:10.1007/s00246-022-02976-z

Cited by 2 publications

(2 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16 Here, we applied our established read-out approach 12 to measure the aortic rupture force in six additional mouse hAD models and compared their aortic rupture force with that of vEDS mice: (i) We used the two most widely investigated mouse models of Marfan syndrome (MFS, OMIM #154700) (Fbn1 C1041G and Fbn1 mgR ), [17][18][19] a rare autosomal-dominant inherited disease with severe cardiovascular manifestations, such as TAAs predisposing to aortic dissection and rupture, caused by mutations in the gene encoding fibrillin-1 (FBN1 in humans, Fbn1 in mice). 20 In one of the two mouse MFS models (Fbn1 mgR ), we also aimed to clarify whether or not the frequently prescribed losartan, which has been shown to slow down aneurysm progression in mouse models as well as humans with MFS, [21][22][23][24][25] also strengthens the potentially weakened thoracic aorta. (ii) Furthermore, we assessed the aortic rupture force in an Efemp2 (encoding fibulin-4 [Fbln4]) smooth-muscle-specific knock-out (SMKO) model recapitulating key vascular phenotypic features (aortic aneurysms and arterial tortuosity) 26 of the autosomal-recessive inherited connective tissue disorder cutis laxa type 1B (OMIM #614437).…”

Section: Ecm Extracellular Matrixmentioning

confidence: 99%

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Dubacher,

Sugiyama,

Smith

et al. 2023

Preprint

View full text Add to dashboard Cite

OBJECTIVE: Hereditary aortic diseases (hADs) increase the risk of aortic dissections and ruptures. Recently, we have established an objective approach to measure the rupture force of the murine aorta, thereby explaining the outcomes of clinical studies and assessing the added value of approved drugs in vascular Ehlers-Danlos syndrome (vEDS). Here, we applied our approach to six additional mouse hAD models. APPROACH AND RESULT: We used two mouse models of Marfan syndrome (MFS) as well as one smooth-muscle-cell-specific knockout (SMKO) of Efemp2 and three CRISPR/Cas9-engineered knock-in models (Ltbp1, Mfap4, and Timp1). Moreover, one of the two MFS models was subjected to 4-week-long losartan treatment. Per mouse, three rings of the thoracic aorta were prepared, mounted on a tissue puller, and uniaxially stretched until rupture. The aortic rupture force of the SMKO and both MFS models was significantly lower compared with wild-type mice but in both MFS models higher than in mice modeling vEDS. In contrast, the Ltbp1, Mfap4, and Timp1 knock-in models presented no impaired aortic integrity. As expected, losartan treatment reduced aneurysm formation but surprisingly had no impact on the aortic rupture force of our MFS mice. CONCLUSIONS: We demonstrate for the first time that our read-out system is able to characterize the aortic biomechanical integrity of mice modeling not only vEDS but also related hADs, allowing the aortic-rupture-force-focused comparison of mouse models. Furthermore, aneurysm progression alone may not be a sufficient read-out for aortic rupture, as blood-pressure-lowering therapies preventing aortic aneurysms might not strengthen the weakened aortic wall. These results may contribute to better medical therapies of hADs.

show abstract

Section: Ecm Extracellular Matrixmentioning

confidence: 99%

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Dubacher,

Sugiyama,

Smith

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…16 Here, we applied our established read-out approach 12 to measure the aortic rupture force in six additional mouse hAD models and compared their aortic rupture force with that of vEDS mice: (1) we used the two most widely investigated mouse models of Marfan syndrome (MFS; OMIM #154700) (Fbn1 C1041G and Fbn1 mgR ), [17][18][19] a rare autosomal-dominant disease with severe cardiovascular manifestations, such as TAAs predisposing to aortic dissection and rupture, caused by mutations in the gene encoding fibrillin-1 (FBN1 in humans, Fbn1 in mice). 20 In one of the two mouse MFS models (Fbn1 mgR ), we also aimed to clarify whether or not the frequently prescribed losartan, which has been shown to slow down aneurysm progression in mouse models as well as humans with MFS, [21][22][23][24][25] also strengthens the potentially weakened thoracic aorta. (2) Furthermore, we assessed the aortic rupture force in an Efemp2 (encoding fibulin-4 [Fbln4]) smooth-muscle-specific knockout (SMKO) model recapitulating key vascular phenotypic features (aortic aneurysms and arterial tortuosity) 26 of the autosomal-recessive connective tissue disorder cutis laxa type 1B (OMIM #614437).…”

mentioning

confidence: 99%

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Dubacher,

Sugiyama,

Smith

et al. 2024

Thromb Haemost

View full text Add to dashboard Cite

Objective Hereditary aortic diseases (hADs) increase the risk of aortic dissections and ruptures. Recently, we have established an objective approach to measure the rupture force of the murine aorta, thereby explaining the outcomes of clinical studies and assessing the added value of approved drugs in vascular Ehlers–Danlos syndrome (vEDS). Here, we applied our approach to six additional mouse hAD models. Material and Methods We used two mouse models (Fbn1C1041G and Fbn1mgR ) of Marfan syndrome (MFS) as well as one smooth-muscle-cell-specific knockout (SMKO) of Efemp2 and three CRISPR/Cas9-engineered knock-in models (Ltbp1, Mfap4, and Timp1). One of the two MFS models was subjected to 4-week-long losartan treatment. Per mouse, three rings of the thoracic aorta were prepared, mounted on a tissue puller, and uniaxially stretched until rupture. Results The aortic rupture force of the SMKO and both MFS models was significantly lower compared with wild-type mice but in both MFS models higher than in mice modeling vEDS. In contrast, the Ltbp1, Mfap4, and Timp1 knock-in models presented no impaired aortic integrity. As expected, losartan treatment reduced aneurysm formation but surprisingly had no impact on the aortic rupture force of our MFS mice. Conclusion Our read-out system can characterize the aortic biomechanical integrity of mice modeling not only vEDS but also related hADs, allowing the aortic-rupture-force-focused comparison of mouse models. Furthermore, aneurysm progression alone may not be a sufficient read-out for aortic rupture, as antihypertensive drugs reducing aortic dilatation might not strengthen the weakened aortic wall. Our results may enable identification of improved medical therapies of hADs.

show abstract

Pediatric Heart Network Trial of Losartan vs. Atenolol in Children and Young Adults with Marfan Syndrome: Impact on Prescription Practices

Cited by 2 publications

References 26 publications

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Contact Info

Product

Resources

About