Publications by authors named "Harry C Dietz"

188 Publications

A seX(X/Y) Article on Marfan Syndrome.

J Am Heart Assoc 2020 10 16;9(20):e018814. Epub 2020 Oct 16.

McKusick-Nathans Department of Genetic Medicine and Howard Hughes Medical Institute Johns Hopkins University School of Medicine Baltimore MD.

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http://dx.doi.org/10.1161/JAHA.120.018814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763377PMC
October 2020

Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

J Pediatr 2020 07;222:213-220.e5

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Departments of Pharmacology and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.

Objective: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial.

Study Design: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models.

Results: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status.

Conclusions: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
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http://dx.doi.org/10.1016/j.jpeds.2020.03.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323908PMC
July 2020

A positively selected FBN1 missense variant reduces height in Peruvian individuals.

Nature 2020 06 13;582(7811):234-239. Epub 2020 May 13.

Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

On average, Peruvian individuals are among the shortest in the world. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.
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http://dx.doi.org/10.1038/s41586-020-2302-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410362PMC
June 2020

Safety and outcome of gastrostomy tube placement in patients with Loeys-Dietz syndrome.

BMC Gastroenterol 2020 Mar 12;20(1):71. Epub 2020 Mar 12.

Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins University School of Medicine, CMSC 2-116, 600 North Wolfe Street, Baltimore, MD, 21287, USA.

Background: Loeys-Dietz syndrome (LDS) is a systemic connective tissue disease (CTD) associated with a predisposition for intestinal inflammation, food allergy, and failure to thrive, often necessitating nutritional supplementation via gastrostomy tube. Poor wound healing has also been observed in in some patients with CTD, potentially increasing the risk of surgical interventions. We undertook to determine the safety and efficacy of gastrostomy tube placement in this population.

Methods: We performed a retrospective cohort study of 10 LDS patients who had a total of 12 gastrostomy tubes placed.

Results: No procedural complications occurred, although one patient developed buried bumper syndrome in the near post-procedural time period and one patient had a small abscess at a surgical stitch. Most patients exhibited improvements in growth, with a median immediate improvement in BMI Z-score of 0.2 per month following the institution of gastrostomy tube feedings. Those with uncontrolled inflammation due to inflammatory bowel disease or eosinophilic gastrointestinal disease showed the least benefit and in some cases failed to demonstrate significant weight gain despite nutritional supplementation.

Conclusions: Gastrostomy tube placement (surgical or endoscopic) is a generally safe and a reasonable therapeutic option for patients with LDS despite their underlying CTD.
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http://dx.doi.org/10.1186/s12876-020-01213-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066767PMC
March 2020

Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β.

Sci Immunol 2019 11;4(41)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of , the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' T17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of or , further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to and for the TGF-β-dependent homeostasis of connective tissues.
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http://dx.doi.org/10.1126/sciimmunol.aax7965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014825PMC
November 2019

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome.

J Clin Invest 2020 02;130(2):686-698

Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-α 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 2 mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glycine substitutions analogous to those found in patients, and we 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 PKCβ prevented death due to spontaneous aortic rupture. Additionally, we found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, was 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.
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http://dx.doi.org/10.1172/JCI130730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994142PMC
February 2020

Management of the aortic arch in patients with Loeys-Dietz syndrome.

J Thorac Cardiovasc Surg 2020 Nov 9;160(5):1166-1175. Epub 2019 Sep 9.

Division of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, Md. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jtcvs.2019.07.130DOI Listing
November 2020

Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis.

Sci Transl Med 2019 07;11(501)

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

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-β (TGFβ) 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 TGFβ-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 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.
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http://dx.doi.org/10.1126/scitranslmed.aau2814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351287PMC
July 2019

Epigenetic activation and memory at a enhancer in systemic sclerosis.

Sci Transl Med 2019 06;11(497)

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

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-β2 () enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFβ2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of 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 , a major profibrotic cytokine.
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http://dx.doi.org/10.1126/scitranslmed.aaw0790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995475PMC
June 2019

Regenerative and durable small-diameter graft as an arterial conduit.

Proc Natl Acad Sci U S A 2019 06 10;116(26):12710-12719. Epub 2019 Jun 10.

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

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.
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http://dx.doi.org/10.1073/pnas.1905966116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601275PMC
June 2019

Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome.

Sci Transl Med 2019 05;11(490)

Center for Medical Genetics, Johns Hopkins University, Baltimore, MD 21287, USA.

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.
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http://dx.doi.org/10.1126/scitranslmed.aat4822DOI Listing
May 2019

Valve-sparing aortic root replacement in children: Outcomes from 100 consecutive cases.

J Thorac Cardiovasc Surg 2019 03 10;157(3):1100-1109. Epub 2018 Dec 10.

Division of Cardiac Surgery, The Johns Hopkins Hospital, Baltimore, Md.

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.
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http://dx.doi.org/10.1016/j.jtcvs.2018.09.148DOI Listing
March 2019

Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma.

Nat Commun 2019 03 8;10(1):1128. Epub 2019 Mar 8.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA.

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-SMAMFBs 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.
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http://dx.doi.org/10.1038/s41467-019-09101-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408468PMC
March 2019

Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene.

Eur J Hum Genet 2019 07 28;27(7):1033-1043. Epub 2019 Feb 28.

Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

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.
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http://dx.doi.org/10.1038/s41431-019-0364-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777542PMC
July 2019

Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome.

J Clin Invest 2019 02 7;129(2):659-675. Epub 2019 Jan 7.

McKusick-Nathans Institute of Genetic Medicine.

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-β (TGF-β) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-β 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-β, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-β ligands. The preserved TGF-β 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.
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http://dx.doi.org/10.1172/JCI123547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355234PMC
February 2019

Pregnancy after Aortic Root Replacement in Marfan's Syndrome: A Case Series and Review of the Literature.

AJP Rep 2018 Oct 18;8(4):e234-e240. Epub 2018 Oct 18.

Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

 We sought to characterize pregnancy-related aortic complications in women with Marfan's syndrome who had prior aortic root replacement.  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.  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.  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.
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http://dx.doi.org/10.1055/s-0038-1675347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193806PMC
October 2018

ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.

Nat Genet 2019 01 19;51(1):42-50. Epub 2018 Nov 19.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%) that frequently presents with ascending aortic aneurysm (AscAA). 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 AscAA, 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.
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http://dx.doi.org/10.1038/s41588-018-0265-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309588PMC
January 2019

First evidence of maternally inherited mosaicism in TGFBR1 and subtle primary myocardial changes in Loeys-Dietz syndrome: a case report.

BMC Med Genet 2018 09 15;19(1):170. Epub 2018 Sep 15.

Mechanical Assistance Device and Artificial Heart Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.

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.
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http://dx.doi.org/10.1186/s12881-018-0661-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139163PMC
September 2018

Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection.

J Am Coll Cardiol 2018 08;72(6):605-615

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Cardiology, Ghent University Hospital, Ghent, Belgium. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacc.2018.04.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378369PMC
August 2018

Proteomics reveals Rictor as a noncanonical TGF-β signaling target during aneurysm progression in Marfan mice.

Am J Physiol Heart Circ Physiol 2018 11 13;315(5):H1112-H1126. Epub 2018 Jul 13.

Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, California.

The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1) 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)-β-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 Thr in a separate cohort of mice and showed in vitro that TGF-β activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of β-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that β-integrin expression and activation modulated TGF-β-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-β 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 β-integrin constitute a modulator of transforming growth factor-β-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells.
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http://dx.doi.org/10.1152/ajpheart.00089.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335018PMC
November 2018

Decreased mitochondrial respiration in aneurysmal aortas of Fibulin-4 mutant mice is linked to PGC1A regulation.

Cardiovasc Res 2018 11;114(13):1776-1793

Department of Vascular Surgery, Erasmus MC, Wytemaweg 80, CN Rotterdam, The Netherlands.

Aim: Thoracic aortic aneurysms are a life-threatening condition often diagnosed too late. To discover novel robust biomarkers, we aimed to better understand the molecular mechanisms underlying aneurysm formation.

Methods And Results: In Fibulin-4R/R mice, the extracellular matrix protein Fibulin-4 is 4-fold reduced, resulting in progressive ascending aneurysm formation and early death around 3 months of age. We performed proteomics and genomics studies on Fibulin-4R/R mouse aortas. Intriguingly, we observed alterations in mitochondrial protein composition in Fibulin-4R/R aortas. Consistently, functional studies in Fibulin-4R/R vascular smooth muscle cells (VSMCs) revealed lower oxygen consumption rates, but increased acidification rates. Yet, mitochondria in Fibulin-4R/R VSMCs showed no aberrant cytoplasmic localization. We found similar reduced mitochondrial respiration in Tgfbr-1M318R/+ VSMCs, a mouse model for Loeys-Dietz syndrome (LDS). Interestingly, also human fibroblasts from Marfan (FBN1) and LDS (TGFBR2 and SMAD3) patients showed lower oxygen consumption. While individual mitochondrial Complexes I-V activities were unaltered in Fibulin-4R/R heart and muscle, these tissues showed similar decreased oxygen consumption. Furthermore, aortas of aneurysmal Fibulin-4R/R mice displayed increased reactive oxygen species (ROS) levels. Consistent with these findings, gene expression analyses revealed dysregulation of metabolic pathways. Accordingly, blood ketone levels of Fibulin-4R/R mice were reduced and liver fatty acids were decreased, while liver glycogen was increased, indicating dysregulated metabolism at the organismal level. As predicted by gene expression analysis, the activity of PGC1α, a key regulator between mitochondrial function and organismal metabolism, was downregulated in Fibulin-4R/R VSMCs. Increased TGFβ reduced PGC1α levels, indicating involvement of TGFβ signalling in PGC1α regulation. Activation of PGC1α restored the decreased oxygen consumption in Fibulin-4R/R VSMCs and improved their reduced growth potential, emphasizing the importance of this key regulator.

Conclusion: Our data indicate altered mitochondrial function and metabolic dysregulation, leading to increased ROS levels and altered energy production, as a novel mechanism, which may contribute to thoracic aortic aneurysm formation.
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http://dx.doi.org/10.1093/cvr/cvy150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198735PMC
November 2018

Carotid Artery Tortuosity Index Is Associated With the Need for Early Aortic Root Replacement in Patients With Loeys-Dietz Syndrome.

J Comput Assist Tomogr 2018 Sep/Oct;42(5):747-753

From the The Russell H. Morgan Department of Radiology and Radiological Science.

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.
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http://dx.doi.org/10.1097/RCT.0000000000000764DOI Listing
September 2018

Spondylolisthesis is Common, Early, and Severe in Loeys-Dietz Syndrome.

J Pediatr Orthop 2018 Sep;38(8):e455-e461

Departments of Pediatrics.

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.
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http://dx.doi.org/10.1097/BPO.0000000000001203DOI Listing
September 2018

Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice.

JCI Insight 2017 08 3;2(15). Epub 2017 Aug 3.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-β ligands, with increased TGF-β signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-β, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-β ligand expression that culminates in both autocrine and paracrine overdrive of TGF-β signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation.
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http://dx.doi.org/10.1172/jci.insight.91588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543913PMC
August 2017

Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: as an Important Contributor.

Front Physiol 2017 13;8:400. Epub 2017 Jun 13.

Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium.

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as , and . Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., ) or in syndromic (e.g., ) or non-syndromic (e.g., ) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort ( = 441; BAV in addition to an aortic root or ascendens diameter ≥ 4.0 cm in adults, or a Z-score ≥ 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation ( = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was ( = 0.002), with 2.5% ( = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of mutations to the etiology of the BAV/TAA phenotype.
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http://dx.doi.org/10.3389/fphys.2017.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469151PMC
June 2017

Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase.

Sci Transl Med 2017 06;9(393)

Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Biallelic mutations in cause pseudoxanthoma elasticum (PXE), a disease characterized by calcification in the skin, eyes, and blood vessels. The function of ATP-binding cassette C6 (ABCC6) and the pathogenesis of PXE remain unclear. We used mouse models and patient fibroblasts to demonstrate genetic interaction and shared biochemical and cellular mechanisms underlying ectopic calcification in PXE and related disorders caused by defined perturbations in extracellular adenosine 5'-triphosphate catabolism. Under osteogenic culture conditions, mutant cells calcified, suggesting a provoked cell-autonomous defect. Using a conditional knockout mouse model, we excluded the prevailing pathogenic hypothesis that singularly invokes failure of hepatic secretion of an endocrine inhibitor of calcification. Instead, deficiency of in both local and distant cells was necessary to achieve the early onset and penetrant ectopic calcification observed upon constitutive gene targeting. mutant cells additionally had increased expression and activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme that degrades pyrophosphate, a major inhibitor of calcification. A selective and orally bioavailable TNAP inhibitor prevented calcification in mutant cells in vitro and attenuated both the development and progression of calcification in mice in vivo, without the deleterious effects on bone associated with other proposed treatment strategies.
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http://dx.doi.org/10.1126/scitranslmed.aal1669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606141PMC
June 2017

Moderately Elevated Homocysteine Does Not Contribute to Thoracic Aortic Aneurysm in Mice.

J Nutr 2017 07 24;147(7):1290-1295. Epub 2017 May 24.

National Human Genome Research Institute, NIH, Bethesda, MD;

Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5-7% of the population and can be reversed by diet. This approach presupposes that hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA. We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFS mouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA. Murine fibrillin 1 gene () MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk. Cobalamin-restricted mice exhibited significantly higher homocysteine ( < 0.0001) and methylmalonic acid ( < 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet. mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.
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http://dx.doi.org/10.3945/jn.117.251173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483969PMC
July 2017

Aortic Root Replacement for Children With Loeys-Dietz Syndrome.

Ann Thorac Surg 2017 May 31;103(5):1513-1518. Epub 2017 Mar 31.

Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Electronic address:

Background: Loeys-Dietz syndrome (LDS) is an aggressive aortopathy with a proclivity for aortic aneurysm rupture and dissection at smaller diameters than other connective tissue disorders. We reviewed our surgical experience of children with LDS to validate our guidelines for prophylactic aortic root replacement (ARR).

Methods: We reviewed all children (younger than 18 years) with a diagnosis of LDS who underwent ARR at our institution. The primary endpoint was mortality, and secondary endpoints included complications and the need for further interventions.

Results: Thirty-four children with LDS underwent ARR. Mean age at operation was 10 years, and 15 (44%) were female. Mean preoperative root diameter was 4 cm. Three children (9%) had composite ARR with a mechanical prosthesis, and 31 (91%) underwent valve-sparing ARR. Concomitant procedures included arch replacement in 2 (6%), aortic valve repair in 1 (3%), and patent foramen ovale closure in 16 (47%). There was no operative mortality. Two children (6%) required late replacement of the ascending aorta, 5 (15%) required arch replacement, 1 (3%) required mitral valve replacement, and 2 (6%) had coronary button aneurysms/pseudoaneurysms requiring repair. Three children required redo valve-sparing ARR after a Florida sleeve procedure, and 2 had progressive aortic insufficiency requiring aortic valve replacement after a valve-sparing procedure. There were 2 late deaths (6%).

Conclusions: These data confirm the aggressive aortopathy of LDS. Valve-sparing ARR should be performed when feasible to avoid the risks of prostheses. Serial imaging of the arterial tree is critical, given the rate of subsequent intervention.
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http://dx.doi.org/10.1016/j.athoracsur.2017.01.053DOI Listing
May 2017