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1.
Artigo em Inglês | MEDLINE | ID: mdl-31627951

RESUMO

OBJECTIVES: We sought to develop strategies for management of the aortic arch in patients with Loeys-Dietz syndrome (LDS) through a review of our clinical experience with these patients and a comparison with our experience in patients with Marfan syndrome (MFS). METHODS: We reviewed hospital and follow-up records of 79 patients with LDS and compared them with 256 patients with MFS who served as reference controls. RESULTS: In the LDS group, 16% of patients presented initially with acute aortic dissection (AAD) (67% type A, 33% type B) or developed AAD during follow-up, compared with 10% of patients with MFS (95% type A, 5% type B). There was no difference between patients with LDS or MFS in need for subsequent arch interventions after aortic root surgery (46% vs 50%, P = 1.0). Among the patients who never had AAD, the need for arch repair at initial root surgery was greater in patients with LDS (5% vs 0.4%, P = .04), as was the need for any subsequent aortic surgery (12% vs 1.3%, P = .0004). Late mortality in patients with LDS after arch repair was greater than in those patients who had no arch intervention (33% vs 6%, P = .007). CONCLUSIONS: In the absence of dissection, patients with LDS have a greater rate of arch intervention after root surgery than patients with MFS. After a dissection, arch reintervention rates are similar in the 2 groups. Arch intervention portends greater late mortality in LDS.

2.
J Clin Invest ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31639107

RESUMO

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-alpha 1 chain of collagen III. Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. We created two mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glycine substitutions analogous to those found in patients, and showed that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase) are major mediators of vascular pathology.Treatment with pharmacologic inhibitors of ERK1/2 or PKC-beta prevented death due to spontaneous aortic rupture. Additionally, we found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, is rescued by attenuation of oxytocin and androgen signaling, respectively. Taken together, our results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.

3.
Sci Transl Med ; 11(501)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316008

RESUMO

Fibrosis is a common pathologic outcome of chronic disease resulting in the replacement of normal tissue parenchyma with a collagen-rich extracellular matrix produced by myofibroblasts. Although the progenitor cell types and cellular programs giving rise to myofibroblasts through mesenchymal transition can vary between tissues and diseases, their contribution to fibrosis initiation, maintenance, and progression is thought to be pervasive. Here, we showed that the ability of transforming growth factor-ß (TGFß) to efficiently induce myofibroblast differentiation of cultured epithelial cells, endothelial cells, or quiescent fibroblasts is dependent on the induced expression and activity of dimeric calpains, a family of non-lysosomal cysteine proteases that regulate a variety of cellular events through posttranslational modification of diverse substrates. siRNA-based gene silencing demonstrated that TGFß-induced mesenchymal transition of a murine breast epithelial cell line was dependent on induction of expression of calpain 9 (CAPN9), an isoform previously thought to be restricted to the gastrointestinal tract. Mice lacking functional CAPN9 owing to biallelic targeting of Capn9 were viable and fertile but showed overt protection from bleomycin-induced lung fibrosis, carbon tetrachloride-induced liver fibrosis, and angiotensin II-induced cardiac fibrosis and dysfunction. A predicted loss-of-function allele of CAPN9 is common in Southeast Asia, with the frequency of homozygosity matching the prediction of Hardy-Weinberg equilibrium. Together with the highly spatially restricted pattern of CAPN9 expression under physiologic circumstances and the heartiness of the murine knockout, these data provide a strong signature for tolerance of therapeutic strategies for fibrosis aimed at CAPN9 antagonism.

4.
Proc Natl Acad Sci U S A ; 116(26): 12710-12719, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31182572

RESUMO

Despite significant research efforts, clinical practice for arterial bypass surgery has been stagnant, and engineered grafts continue to face postimplantation challenges. Here, we describe the development and application of a durable small-diameter vascular graft with tailored regenerative capacity. We fabricated small-diameter vascular grafts by electrospinning fibrin tubes and poly(ε-caprolactone) fibrous sheaths, which improved suture retention strength and enabled long-term survival. Using surface topography in a hollow fibrin microfiber tube, we enable immediate, controlled perfusion and formation of a confluent endothelium within 3-4 days in vitro with human endothelial colony-forming cells, but a stable endothelium is noticeable at 4 weeks in vivo. Implantation of acellular or endothelialized fibrin grafts with an external ultrathin poly(ε-caprolactone) sheath as an interposition graft in the abdominal aorta of a severe combined immunodeficient Beige mouse model supports normal blood flow and vessel patency for 24 weeks. Mechanical properties of the implanted grafts closely approximate the native abdominal aorta properties after just 1 week in vivo. Fibrin mediated cellular remodeling, stable tunica intima and media formation, and abundant matrix deposition with organized collagen layers and wavy elastin lamellae. Endothelialized grafts evidenced controlled healthy remodeling with delayed and reduced macrophage infiltration alongside neo vasa vasorum-like structure formation, reduced calcification, and accelerated tunica media formation. Our studies establish a small-diameter graft that is fabricated in less than 1 week, mediates neotissue formation and incorporation into the native tissue, and matches the native vessel size and mechanical properties, overcoming main challenges in arterial bypass surgery.

5.
Sci Transl Med ; 11(497)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217334

RESUMO

In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor-ß2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFß2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.

6.
Sci Transl Med ; 11(490)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043570

RESUMO

Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak at term, are sustained after delivery, and might synergize with previously defined signaling pathways implicated in aneurysm progression, we examined the hormone oxytocin, which initiates uterine contraction and milk letdown for the duration of lactation through phosphorylation of extracellular signal-regulated kinase (ERK). In a mouse model of MFS that shows highly penetrant postnatal aortic dissection, risk was strongly attenuated by preventing lactation or use of an oxytocin receptor antagonist. Survival correlated inversely with the extent of ERK activation in the aortic wall, and strong protection was observed upon attenuation of ERK phosphorylation using an inhibitor of ERK kinase (MEK) or the U.S. Food and Drug Administration-approved medication hydralazine, offering potential therapeutic strategies for pregnancy-associated vascular catastrophe in the setting of MFS.

7.
J Thorac Cardiovasc Surg ; 157(3): 1100-1109, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30982542

RESUMO

OBJECTIVE: Valve-sparing root replacement is an attractive alternative to composite mechanical or biologic prostheses for aortic root aneurysms in children. Data on outcomes in pediatric patients are limited. We present our institutional experience with 100 consecutive pediatric valve-sparing aortic root procedures. METHODS: All children who underwent valve-sparing root replacement at our institution from May 1997 to August 2017 were identified, and echocardiographic and clinical data were reviewed. The primary end point was mortality, and secondary end points included complications, further interventions, and subsequent valvular dysfunction. RESULTS: Median age at operation was 13.6 years (interquartile range, 9.42-15.9); 51 patients (51%) had Marfan syndrome, and 39 patients (39%) had Loeys-Dietz syndrome. Mean preoperative maximum sinus diameter was 4.4 ± 0.71 cm (z score 7.3 [5.7-9.3]). Most patients (n = 80, 80%) underwent reimplantation procedures with a Valsalva graft. Four patients (4%) underwent David I reimplantation with a straight-tube graft, 13 patients (13%) underwent a Yacoub remodeling procedure, and 3 patients (3%) underwent a Florida sleeve procedure. Perioperative valve-sparing root replacement mortality was 2% (n = 2). Six patients required late reintervention for development of pseudoaneurysms. Eight patients underwent additional aortic surgery. Average time to reoperation was 7.23 ± 4.56 years. Of the 84 patients undergoing a reimplantation procedure, 5 (5.9%) underwent late valve replacement versus 5 (33.3%) of the 15 patients who received a remodeling procedure (P = .001). CONCLUSIONS: Valve-sparing root replacement is a safe and effective option for children with aortic root aneurysms in children. The reimplantation procedure is preferred. Late aortic insufficiency and pseudoaneurysm formation remain late concerns.

8.
Nat Commun ; 10(1): 1128, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850660

RESUMO

Scleroderma is an autoimmune rheumatic disorder accompanied by severe fibrosis in skin and other internal organs. During scleroderma progression, resident fibroblasts undergo activation and convert to α-smooth muscle actin (α-SMA) expressing myofibroblasts (MFBs) with increased capacity to synthesize collagens and fibrogenic components. Accordingly, MFBs are a major therapeutic target for fibrosis in scleroderma and treatment with blocking MFBs could produce anti-fibrotic effects. TLY012 is an engineered human TNF-related apoptosis-inducing ligand (TRAIL) which induces selective apoptosis in transformed cells expressing its cognate death receptors (DRs). Here we report that TLY012 selectively blocks activation of dermal fibroblasts and induces DR-mediated apoptosis in α-SMA+ MFBs through upregulated DR5 during its activation. In vivo, TLY012 reverses established skin fibrosis to near-normal skin architecture in mouse models of scleroderma. Thus, the TRAIL pathway plays a critical role in tissue remodeling and targeting upregulated DR5 in α-SMA+ MFBs is a viable therapy for fibrosis in scleroderma.


Assuntos
Actinas/genética , Derme/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Escleroderma Sistêmico/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Actinas/metabolismo , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Diferenciação Celular , Colágeno/genética , Colágeno/metabolismo , Derme/metabolismo , Derme/patologia , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Engenharia de Proteínas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Transdução de Sinais
9.
Eur J Hum Genet ; 27(7): 1033-1043, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30820038

RESUMO

Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1-2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. This study aimed at unravelling the contribution of deleterious deletions or duplications in 95 unrelated BAV/TAA patients. Seven unique or rare CNVs were validated, harbouring protein-coding genes with a role in the cardiovascular system. Based on the presence of overlapping CNVs in patients with cardiovascular phenotypes in the DECIPHER database, the identification of similar CNVs in whole-exome sequencing data of 67 BAV/TAA patients and suggested topological domain involvement from Hi-C data, supportive evidence was obtained for two genes (DGCR6 and TBX20) of the seven initially validated CNVs. A rare variant burden analysis using next-generation sequencing data from 637 BAV/TAA patients was performed for these two candidate genes. This revealed a suggestive genetic role for TBX20 in BAV/TAA aetiology, further reinforced by segregation of a rare TBX20 variant with the phenotype within a BAV/TAA family. To conclude, our results do not confirm a significant contribution for deleterious CNVs in BAV/TAA as only one potentially pathogenic CNV (1.05%) was identified. We cannot exclude the possibility that BAV/TAA is occasionally attributed to causal CNVs though, or that certain CNVs act as genetic risk factors by creating a sensitised background for BAV/TAA. Finally, accumulative evidence for TBX20 involvement in BAV/TAA aetiology underlines the importance of this transcription factor in cardiovascular disease.

10.
Eur J Hum Genet ; 27(7): 1044-1053, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30796334

RESUMO

Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA. Intriguingly, patients with craniosynostosis have also been reported to be explained molecularly by similar loss-of-function SMAD6 variants. While significantly reduced penetrance of craniosynostosis has been reported for the SMAD6 variants as such, near-complete penetrance is reached upon co-occurrence with a common BMP2 SNP risk allele. Here, we report on the results of a SMAD6-variant analysis in 473 unrelated non-syndromic TAA patients, of which the SMAD6-positive individuals were also studied for the presence of the BMP2 risk allele. Although only 14% of the TAA patients also presented BAV, all novel likely pathogenic SMAD6 variants (N = 7) were identified in BAV/TAA individuals, further establishing the role of SMAD6 variants to the aetiology of BAV/TAA and revealing limited contribution to TAA development in patients with a tricuspid aortic valve. Familial segregation studies confirmed reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity. None of our six BMP2+/SMAD6+ patients presented with craniosynostosis. Hence, the proposed digenic model for craniosynostosis was not supported in the presented BAV/TAA cohort, suggesting that additional factors are at play. Finally, our data provide improved insights into the clinical spectrum of SMAD6-related BAV/TAA and has important implications for molecular diagnostics.

11.
J Clin Invest ; 129(2): 659-675, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30614814

RESUMO

The aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors of the transforming growth factor-ß (TGF-ß) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-ß receptor I, we found that the effects of this mutation depend on the lineage of origin of vascular smooth muscle cells (VSMCs). Secondary heart field-derived (SHF-derived), but not neighboring cardiac neural crest-derived (CNC-derived), VSMCs showed impaired Smad2/3 activation in response to TGF-ß, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-ß ligands. The preserved TGF-ß signaling potential in CNC-derived VSMCs associated, in vivo, with increased Smad2/3 phosphorylation. CNC-, but not SHF-specific, deletion of Smad2 preserved aortic wall architecture and reduced aortic dilation in this mouse model of LDS. Taken together, these data suggest that aortic root aneurysm predisposition in this LDS mouse model depends both on defective Smad signaling in SHF-derived VSMCs and excessive Smad signaling in CNC-derived VSMCs. This work highlights the importance of considering the regional microenvironment and specifically lineage-dependent variation in the vulnerability to mutations in the development and testing of pathogenic models for aortic aneurysm.

12.
Ophthalmic Genet ; 39(6): 754-758, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30406707

RESUMO

BACKGROUND: Loeys-Dietz syndrome (LDS) is a connective tissue disorder that has phenotypic overlap with Marfan syndrome. In LDS, the aortic root dissections can be more aggressive and occur at a younger age than Marfan syndrome. MATERIALS AND METHODS: Review of two cases. RESULTS: A 7-year old boy with history of LDS was found to have a vitreous hemorrhage in the right eye. Further examination showed findings of Familial Exudative Vitreoretinopathy (FEVR). Both eyes were found to have peripheral non-perfusion and neovascularization. A non-related 25-month-old boy with no molecularly confirmed connective tissue disorder was found to have bilateral peripheral non-perfusion and bilateral tractional retinal detachments. The boy was clinically diagnosed with Larsen syndrome, Ehlers-Danlos syndrome kyphoscoliotic form, and Marfan syndrome before presentation. The FEVR lead to consideration of LDS that was molecularly confirmed. Consequently, he was monitored for aortic root dilation. CONCLUSION: FEVR findings may lead to diagnosis of LDS and patients with LDS may present with proliferative retinopathy.

13.
AJP Rep ; 8(4): e234-e240, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30473905

RESUMO

Objectives We sought to characterize pregnancy-related aortic complications in women with Marfan's syndrome who had prior aortic root replacement. Study Design This is a retrospective case series study and literature review of women with Marfan's syndrome with pregnancy after aortic root replacement. We surveyed women with Marfan's syndrome who had successful pregnancy after aortic root replacement using the Marfan Foundation Website and from two large tertiary care Marfan's clinics. Clinical data, counseling information, and details of pregnancy-related aortic complications were compiled. A literature review was performed assessing aortic outcomes in women with Marfan's syndrome with pregnancy after aortic surgery. Results Fourteen women with 20 pregnancies were identified. Two women had three pregnancies following root replacement for aortic dissection. There were no aortic dissections during the 20 pregnancies. In contrast, aortic dissection was frequently reported in the literature. Conclusions Women with Marfan's syndrome who become pregnant following aortic root replacement remain at risk for distal aortic dissection related to pregnancy. The exact risk is difficult to quantify but is not zero and women should be counseled accordingly.

14.
Nat Genet ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30455415

RESUMO

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%)1-3 that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA5-8, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

15.
BMC Med Genet ; 19(1): 170, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30219046

RESUMO

BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability. CASE PRESENTATION: We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (p.Arg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far. CONCLUSIONS: This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.

17.
J Am Coll Cardiol ; 72(6): 605-615, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30071989

RESUMO

BACKGROUND: Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events. OBJECTIVES: The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework. METHODS: We applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel. RESULTS: Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD. CONCLUSIONS: The ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.

18.
Am J Physiol Heart Circ Physiol ; 315(5): H1112-H1126, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30004239

RESUMO

The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1C1041G/+) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-ß-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingenuity Pathway Analysis of over 1,000 proteins quantified from the in vivo MFS mouse aorta by data-independent acquisition mass spectrometry revealed a predicted upstream regulator, Rictor, that was selectively activated in aged MFS mice. We validated this pattern of Rictor activation in vivo by Western blot analysis for phosphorylation on Thr1135 in a separate cohort of mice and showed in vitro that TGF-ß activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of ß3-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that ß3-integrin expression and activation modulated TGF-ß-induced Rictor phosphorylation in vitro, and this signaling effect was associated with an altered vascular smooth muscle cell proliferative-migratory and metabolic in vitro phenotype that parallels the in vivo aneurysm phenotype in MFS. These results reveal that Rictor is a novel, context-dependent, noncanonical TGF-ß signaling effector with potential pathogenic implications in aortic aneurysm. NEW & NOTEWORTHY We present the most comprehensive quantitative analysis of the ascending aortic aneurysm proteome in Marfan syndrome to date resulting in novel and potentially wide-reaching findings that expression and signaling by ß3-integrin constitute a modulator of transforming growth factor-ß-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells.

19.
J Pediatr Orthop ; 38(8): e455-e461, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29889773

RESUMO

BACKGROUND: We studied the prevalence and treatment outcomes of spondylolisthesis in patients with Loeys-Dietz syndrome (LDS). METHODS: Clinical data and lumbosacral imaging of 138 patients with LDS were reviewed. Spondylolisthesis (L4-L5 or L5-S1) and spondylolysis were characterized by multimodal imaging and correlated with clinical data. Treatments and outcomes were characterized for patients with spondylolisthesis. Associations were determined using the Fisher exact, Mann-Whitney, and Student t tests (α=0.05). RESULTS: Twenty-four patients (17%) had spondylolysis and 23 (17%) had spondylolisthesis. Median age at spondylolisthesis diagnosis was 11 (interquartile range, 9.5) years. In patients in whom measurement was possible (n=20), mean (±SD) slip was 48% (±35%). Nineteen patients had L5-S1 slip and 4 had L4-L5 slip. Of the patients with spondylolisthesis, 5 had no evidence of spondylolysis; of those with spondylolysis, all but 6 had spondylolisthesis. Eleven patients with spondylolisthesis underwent posterior spinal fusion (PSF) to treat slip progression, pain, and/or neurological deficit. Spondylolisthesis recurred in 1 patient who underwent PSF with bone graft arthrodesis alone (no instrumentation). The other 10 patients underwent PSF with instrumentation and fusion. Three patients additionally underwent Bohlman interbody fusion. Two patients developed implant failure. S2 fixation was performed at revision to achieve fusion in these patients. Mean Meyerding grade improved in patients who underwent arthrodesis, from 3.9 (±1.2) to 1.9 (±1.3) (P=0.002). Complications were 2 cerebrospinal fluid leaks, 2 transient postoperative paresthesias, and 1 case each of pseudarthrosis at S1-S2, wound dehiscence, and transient urinary incontinence. No significant associations between LDS type and lumbosacral abnormalities were found. CONCLUSIONS: High-grade spondylolisthesis is common in LDS and usually associated with spondylolysis. Patients requiring surgery for spondylolisthesis present during childhood and do well after instrumented PSF. Interbody fusion and stabilization of S1 and S2 can prevent physeal deformation. LDS should be considered in patients with high-grade spondylolisthesis. Patients with LDS should be monitored for spondylolisthesis and spondylolysis starting when they are young. LEVEL OF EVIDENCE: Level IV-retrospective study.


Assuntos
Síndrome de Loeys-Dietz/complicações , Vértebras Lombares/diagnóstico por imagem , Sacro/diagnóstico por imagem , Fusão Vertebral/estatística & dados numéricos , Espondilolistese/etiologia , Adolescente , Adulto , Baltimore/epidemiologia , Transplante Ósseo , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Síndrome de Loeys-Dietz/diagnóstico por imagem , Vértebras Lombares/cirurgia , Região Lombossacral/diagnóstico por imagem , Masculino , Complicações Pós-Operatórias , Prevalência , Pseudoartrose , Radiografia , Estudos Retrospectivos , Espondilolistese/diagnóstico por imagem , Espondilolistese/epidemiologia , Espondilolistese/cirurgia , Espondilólise , Resultado do Tratamento , Adulto Jovem
20.
J Comput Assist Tomogr ; 42(5): 747-753, 2018 Sep/Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29901510

RESUMO

OBJECTIVE: This study aimed to determine if carotid arterial tortuosity represents a marker of disease severity in Loeys-Dietz syndrome (LDS). METHODS: Fifty-four 54 LDS patients (mean age, 17.0 years) who underwent computed tomogram angiography from January 2004 to December 2013 were retrospectively identified. Carotid artery tortuosity index (CATI) was calculated from computed tomogram angiography. Clinical variables were obtained from the medical records. Relationship between CATI and need for aortic root replacement was evaluated with Cox proportional hazard model and Kaplan-Meier analysis. RESULTS: Higher CATI was associated with the need for aortic root replacement (P < 0.001) in the univariate Cox proportional hazard model. Patients were stratified based on both CATI and aortic root size in Kaplan-Meier analysis, and patients with higher CATI were more likely to require aortic root replacement (P < 0.001) in both aortic root size strata. CONCLUSION: Increased carotid artery tortuosity is associated with the need for early aortic root replacement in patients with LDS.


Assuntos
Aorta/cirurgia , Artérias Carótidas/anormalidades , Artérias Carótidas/diagnóstico por imagem , Síndrome de Loeys-Dietz/complicações , Adolescente , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença
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