Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients With the Marfan Syndrome

Tierney, Elif Seda Selamet; Levine, Jami C.; Sleeper, Lynn A.; Roman, Mary J.; Bradley, Timothy J.; Colan, Steven D.; Chen, Shan; Campbell, Michael J.; Cohen, Meryl S.; Backer, Julie De; Heydarian, Haleh; Hoskoppal, Arvind; Lai, Wyman W.; Liou, Aimée; Marcus, Edward; Nutting, Arni; Olson, Aaron K.; Parra, David; Pearson, Gail D.; Pierpont, Mary Ella M; Printz, Beth F.; Pyeritz, Reed E.; Ravekes, William; Sharkey, Angela M.; Srivastava, Shubhika; Young, Luciana; Lacro, Ronald V.

doi:10.1016/j.amjcard.2018.01.016

Cited by 35 publications

(39 citation statements)

References 26 publications

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“…82 Therefore, it is surprising that a recent follow-up study of the largest clinical trial assessing losartan versus atenolol in patients with MFS found that treatment with atenolol >3 years decreased baseline aortic root stiffness, whereas losartan did not. 29,83 This study also found that patients with MFS with higher baseline stiffness measurements had the fastest rate of growth of the aortic root. Although these results favor the use of β-blockers over Atr1 inhibition to prevent aortic growth in patients with MFS, it remains unclear why an Atr1 blocker failed to block aortic stiffness.…”

Section: Closing Remarks and Future Perspectivessupporting

confidence: 55%

Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections

Milewicz

Ramirez

2019

ATVB

103

109

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Thoracic aortic aneurysms that progress to acute aortic dissections are often fatal. Thoracic aneurysms have been managed with treatment with β-adrenergic blocking agents (β-blockers) and routine surveillance imaging, followed by surgical repair of the aneurysm when the risk of dissection exceeds the risk for repair. Thus, there is a window to initiate therapies to slow aortic enlargement and delay or ideally negate the need for surgical repair of the aneurysm to prevent a dissection. Mouse models of Marfan syndrome—a monogenic disorder predisposing to thoracic aortic disease—have been used extensively to identify such therapies. The initial fi that TGFβ (transformation growth factor-β) signaling was increased in the aortic media of a Marfan syndrome mouse model and that its inhibition via TGFβ neutralization or At1r (Ang II [angiotensin II] type I receptor) antagonism prevented aneurysm development was generally viewed as a groundbreaking discovery that could be translated into the first cure of thoracic aortic disease. However, several large randomized trials of pediatric and adult patients with Marfan syndrome have subsequently yielded no evidence that At1r antagonism by losartan slows aortic enlargement more effectively than conventional treatment with β-blockers. Subsequent studies in mouse models have begun to resolve the complex molecular pathophysiology underlying onset and progression of aortic disease and have emphasized the need to preserve TGFβ signaling to prevent aneurysm formation. This review describes critical experiments that have influenced the evolution of our understanding of thoracic aortic disease, in addition to discussing old controversies and identifying new therapeutic opportunities.

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Section: Closing Remarks and Future Perspectivessupporting

confidence: 55%

Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections

Milewicz

Ramirez

2019

ATVB

103

109

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“…Perhaps unintuitively, increased stiffness (resistance to deformation) can associate with decreased vessel strength (ability to withstand stress without breaking), with one study measuring an approximately 30% decrease in vessel strength accompanied by a 72% increase in stiffness in aneurysmal versus nonaneurysmal ascending aorta [374,375]. Correlations between increased stiffness and aortic dilatation have been reported in numerous studies of both patients and mouse models of TAA [376][377][378][379][380][381][382][383][384][385][386][387][388][389][390].…”

Section: Adaptive and Maladaptive Roles Of "Aortic Stiffness"mentioning

confidence: 99%

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

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Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

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“…In MFS patients, endothelial dysfunction and increased aortic stiffness are associated with aortic aneurysmal formation [ 48 , 49 , 50 ], and losartan attenuates impairment of endothelial function in MFS mice and patients ( Figure 3 ). Sellers et al reported that Fbn1 C1039G/+ mice crossed with hypotensive Agt1ar knockout mice ( Fbn1 C1039G/+ : Agt1ar −/− ) showed unabated aortic aneurysmal formation [ 51 ].…”

Section: Marfan Syndromementioning

confidence: 99%

TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections

Takeda

Hara

Fujiwara

et al. 2018

IJMS

109

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Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 (TGFBR1 and TGFBR2) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders.

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Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients With the Marfan Syndrome

Cited by 35 publications

References 26 publications

Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections

Therapies for Thoracic Aortic Aneurysms and Acute Aortic Dissections

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections

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