A Novel Murine Model of Marfan Syndrome Accelerates Aortopathy and Cardiomyopathy

Cavanaugh, Nicholas B.; Lei, Qian; Westergaard, Nicole M.; Kutschke, William; Born, Ella; Turek, Joseph W.

doi:10.1016/j.athoracsur.2016.10.077

Cited by 18 publications

(12 citation statements)

References 35 publications

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“…In addition, the angiotensin-converting enzyme (ACE) inhibitor enalapril, which blocks AngII formation, did not adequately inhibit aneurysm formation, regardless of the same antihypertensive effect as losartan [ 40 ]. Furthermore, Cavanaugh et al reported that subpressor doses of AngII could accelerate aneurysmal formation and dissection in Fbn1 C1039G/+ mice [ 41 ]. These observations suggested that losartan may exert favorable effects via activating or preserving AT 2 R signal cascades.…”

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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Section: Marfan Syndromementioning

confidence: 99%

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

Takeda

Hara

Fujiwara

et al. 2018

IJMS

109

View full text Add to dashboard Cite

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“…Mild LV dilatation, independent of valvular dysfunction, was also observed by Campens et al [ 11 ] in the same mouse model using ultrasound analysis. In other studies by Cavanaugh et al [ 20 ] and Rouf et al [ 21 ], a significant increase in the LV diameter of Fbn1 C1039G/+ mice was only observed after a two-week angiotensin II treatment, or after surgical constriction of the thoracic aorta, respectively. Cook et al [ 22 ], on the other hand, identified a severe primary dilated cardiomyopathy with significant systolic dysfunction in the Fbn1 mgR/mgR mouse model.…”

Section: Introductionmentioning

confidence: 75%

Spontaneous Right Ventricular Pseudoaneurysms and Increased Arrhythmogenicity in a Mouse Model of Marfan Syndrome

Steijns

Renard

Vanhomwegen

et al. 2020

IJMS

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Patients with Marfan syndrome (MFS), a connective tissue disorder caused by pathogenic variants in the gene encoding the extracellular matrix protein fibrillin-1, have an increased prevalence of primary cardiomyopathy, arrhythmias, and sudden cardiac death. We have performed an in-depth in vivo and ex vivo study of the cardiac phenotype of Fbn1mgR/mgR mice, an established mouse model of MFS with a severely reduced expression of fibrillin-1. Using ultrasound measurements, we confirmed the presence of aortic dilatation and observed cardiac diastolic dysfunction in male Fbn1mgR/mgR mice. Upon post-mortem examination, we discovered that the mutant mice consistently presented myocardial lesions at the level of the right ventricular free wall, which we characterized as spontaneous pseudoaneurysms. Histological investigation demonstrated a decrease in myocardial compaction in the MFS mouse model. Furthermore, continuous 24 h electrocardiographic analysis showed a decreased heart rate variability and an increased prevalence of extrasystolic arrhythmic events in Fbn1mgR/mgR mice compared to wild-type littermates. Taken together, in this paper we document a previously unreported cardiac phenotype in the Fbn1mgR/mgR MFS mouse model and provide a detailed characterization of the cardiac dysfunction and rhythm disorders which are caused by fibrillin-1 deficiency. These findings highlight the wide spectrum of cardiac manifestations of MFS, which might have implications for patient care.

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“…Likewise, they support the hypothesis previously reported that the canonical TGF-β signaling contributes to this load-induced cardiac decompensation 16 . An interesting novel in vivo mouse model of Cavanaugh et al consisting of subcutaneously delivered angiotensin II in MFS mice causes accelerated aortic aneurysm formation and dilated cardiomyopathy even without aortic insufficiency, suggesting a potential intrinsic aetiology for the diseased myocardium 21 .…”

Section: Discussionmentioning

confidence: 99%

Postsystolic thickening is a potential new clinical sign of injured myocardium in marfan syndrome

Mas‐Stachurska

Egea

Bruin-Bon

et al. 2021

Sci Rep

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The mechanisms leading to cardiac remodeling in Marfan syndrome (MFS) are a matter of debate since it could be either due to structural dysfunction of the myocardial extracellular matrix or to increased afterload caused by the dilated aorta. We aim to characterize the presence of abnormal myocardial function in MFS and to investigate its potential association with increased afterload. Aorta, left ventricle (LV) and the postsystolic thickening (PST) were analyzed in echocardiography in Fbn1C1039G/+ mice and in patients with MFS in comparison with wild type (WT) mice and healthy humans. PST was more frequent in MFS than in WT mice (p < 0.05). MFS mice with PST showed larger aorta than those without PST. Patients with MFS showed larger aorta, poorer LV function and a higher prevalence of PST (56%) than did the healthy controls (23%); p = 0.003. Blood pressure was similar. The higher prevalence of PST in an experimental murine model and in MFS patients, regardless of systemic arterial pressure, suggests an increased afterload on the LV myocardium. This finding supports the use of PST as an indicator of myocardial damage and encourage searching for novel early preventive therapy.

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A Novel Murine Model of Marfan Syndrome Accelerates Aortopathy and Cardiomyopathy

Cited by 18 publications

References 35 publications

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

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

Spontaneous Right Ventricular Pseudoaneurysms and Increased Arrhythmogenicity in a Mouse Model of Marfan Syndrome

Postsystolic thickening is a potential new clinical sign of injured myocardium in marfan syndrome

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