Loeys-Dietz Syndrome Patients Research Articles

Natural history and growth rate of intracranial aneurysms in Loeys-Dietz syndrome: implications for treatment.

Loeys-Dietz syndrome (LDS) is a heritable aortopathy associated with craniofacial abnormalities and dilatation and dissection of the aorta and its branches, as well as increased risk for intracranial aneurysms (ICAs). Given the rarity of the disease, the authors aimed to better define the natural history and role for the treatment for ICAs in these patients. The medical records of 83 patients with LDS were retrospectively reviewed to obtain clinical and genetic history and vascular imaging of the aorta, aortic branches, and intracranial vessels. Serial radiology reports and cervical and intracranial vascular images were reviewed to determine presence, location, and size of ICAs. In total, 55 patients (66.3%) had at least two screening intracranial vascular examinations, and 19 (22.9%) had at least 1 ICA detected. Aneurysms were typically small (mean ± SD 3.2 ± 1.8 mm). ICAs were most often located in the cavernous carotid, followed by the ophthalmic and anterior cerebral artery vessels. The rate of ICA growth was 0.43 ± 0.53 mm/year, similar to that of the general population. Three patients underwent intervention for an ICA, with 1 procedure complicated by stroke and resulting in transient hemiparesis. Several illustrative cases detail the authors' experience with ICA growth, de novo aneurysm formation, and ICA intervention in this rare patient population. ICAs in patients with LDS are common, are frequently small, and have a growth rate similar to that of unruptured ICAs in the general population. More aggressive or earlier intervention for asymptomatic ICAs identified in LDS patients compared with the general population is likely unwarranted based on the authors' experience at their institution.

Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation.

Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis. Investigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants. A retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts. Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P= 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0years [IQR 29.0-47.0] in individuals with DN variants in MH2, compared to 46.0years [IQR 40.0-54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines. Distinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs.

Impact of Genotype-Phenotype Interactions on Cardiovascular Function in Paediatric Loeys-Dietz Syndrome

BackgroundThe relationship between genotype and phenotypical vascular and cardiac properties in paediatric Loeys-Dietz syndrome (LDS) patients are not well characterized. This study explores the phenotypical differences in aortic properties and cardiac structural and functional parameters between paediatric LDS patients with TGFBR1 and TGFBR2 mutations. MethodsWe included 32 LDS patients with either TGFBR1 (n = 17) or TGFBR2 (n = 15) mutations. Echocardiographic data included aortic dimensions, distensibility, strain, and stiffness at the level of the annulus, sinuses of Valsalva, sinotubular junction, ascending aorta, and descending aorta. Parameters for left ventricular size and function were also recorded. ResultsDemographics were similar between the groups. Patients with TGFBR2 were more likely to have undergone aortic surgery (47% vs 12%, P = 0.057) and use angiotensin receptor blockers (93% vs 47%, P = 0.015). Aortic z scores were significantly larger in the TGFBR2 group at the level of the aortic valve annulus (P = 0.007), sinuses of Valsalva (P = 0.001), sinotubular junction (P = 0.001), and ascending aorta (P = 0.054). Patients with TGFBR2 also had significantly lower aortic distensibility and strain coupled with higher stiffness index at the level of the annulus, sinotubular junction, and ascending aorta. Parameters for the descending aorta, cardiac morphology, and cardiac function were similar between the groups. ConclusionsPaediatric LDS patients with TGFBR2 present with more severe cardiovascular phenotypes than patients with TGFBR1 with larger aortic dimensions and increased aortic stiffness. Our findings suggest that genotypes should be taken into consideration in the clinical management of paediatric LDS patients.

Cardiovascular involvement and prognosis in Loeys-Dietz syndrome.

Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder associated with aortic root enlargement and risk of thoracic aortic dissection (AD). Genetic examination is essential for diagnosis. Analysis of clinical data on cardiovascular involvement and management of LDS patients. The study included carriers of LDS-associated genetic variants, identified between 2012 and 2022. Assessment of cardiovascular involvement was based on echocardiography and computed tomography angiography with quantitative assessment of arterial tortuosity. Involvement of other systems was also evaluated. We noted major cardiovascular events, including aortic events, defined as AD, elective aortic surgery or otherwise unexplained sudden death. 34 patients from 15 families were included, five identified variants were novel. Probands' mean age was 41 years. Cardiovascular abnormalities, aortic involvement, aortic tortuosity and tortuosity of cervical arteries were present in 79, 71, 68 and 100% of carriers, respectively. First aortic events (9 A-type AD, 6 elective thoracic aortic surgeries, and one sudden death) occurred in 16 (47%) patients at median age of 35 years. The youngest age at AD was 16 years, and 7 years at elective aneurysm repair. Second and third aortic event occurred in 9 and 4 patients, respectively. 8 patients (24%) experienced other major cardiovascular events. Aortic event-free survival was shorter in presence of skin striae (p=0.03), tended to be shorter in presence of marfanoid features (p=0.06), and longer with TGFB2 variants (p=0.06). LDS is associated with high burden of cardiovascular complications at young age.

IPSC-derived vascular smooth muscle cell model recapitulates Loeys-Dietz-Syndrome type V aortic phenotype

Abstract Introduction Thoracic aortic aneurysm and dissection (TAAD) is a hallmark of Loeys-Dietz syndrome (LDS) and a prominent cause of morbidity and sudden death. Current drug therapies are only able to slow down but not stop or reverse aneurysm formation. TAAD pathomechanisms remain largely elusive, complicating the development of more effective treatments. Purpose The creation of a disease-relevant in vitro model, that recapitulates the disease phenotype, is incredibly valuable to gain better insights in the pathomechanisms underlying TAAD and to develop new treatments. Methods Validated induced pluripotent stem cells (iPSCs) of two male TAAD patients carrying the same pathogenic p.Asp263His variant in TGFB3 (LDS type V) and one male healthy individual were used in this study. One patient underwent a Bentall procedure at age 66 years because of insufficiency of a bicuspid aortic valve and TAA (50 mm, z-score= 5.2). The second patient presented with a type A dissection at age 31 years, also requiring Bentall surgery. The patients are distantly related, having a common ancestor allele, estimated to be arisen >400 years ago. We created and characterized iPSC-derived neural crest-vascular smooth muscle cell (NC-VSMC) lines from both LDS type V patients and the healthy control. Addition of a chemical thromboxane A2 receptor agonist initiated NC-VSMC contraction which was quantified by the change in impedance using the xCELLigence system and RTCA software. Additionally, the proliferation rate was quantified with the CyQuant Direct Cell Proliferation Assay Kit and inverted DMi8 fluorescence microscope (Leica). With an univariate ANOVA test, we assessed similarity of the variance between groups, after which the corresponding two-way t-test was performed. Results Within 30 minutes after thromboxane A2 receptor agonist addition, a maximal contracted state was reached, which was significantly lower for the first patient (2 clones) as compared to the control (2 cloness) (p=0.03). The time to get to this maximal contracted state was comparable between patient and control, while the surface area coverage over a duration of 1h stimulation was reduced for patient NC-VSMCs (p=0.04). Contraction of the NC-VSMC line (1 clone) from the second LDS patient did not significantly differ from the contraction profile of the control line. After one hour, U46619 was removed resulting in relaxation and full recovery for all NC-VSMCs. Proliferation rate of NC-VSMCs from all patient and control lines was around 1.5, with no significant difference between the groups (p=0.59). Conclusion We created an NC-VSMC model that recapitulates the LDS aortic phenotype with regards to reduced VSMC contractility. Although NC-VSMC lines created from the same individual showed extremely little variability, there is important variability between the lines of different patients which might be due to immaturity of the cells, environmental factors and the presence of genetic modifiers.

Mitral annular disjunction on cardiac MRI: Prevalence and association with disease severity in Loeys-Dietz syndrome

BackgroundThe purpose of this study was to evaluate mitral annular disjunction (MAD) on cardiac magnetic resonance imaging (MRI) in Loeys-Dietz Syndrome (LDS) and to explore its association with adverse outcomes. MethodsIn this retrospective cohort study, adult patients with LDS who underwent cardiac MRI were evaluated for MAD, aortic dimensions, and ventricular volumetry. Aortic events were defined as aortic surgery and/or dissection and severe arrhythmic events as cardiac arrest or sustained ventricular tachycardia (VT). ResultsAmong 46 LDS patients (52% female, 37.2 ± 14.3 years), 17 had MAD (37%). MAD and no MAD groups were similar in age, sex, aortic dimensions and left ventricular parameters. After a clinical follow-up of 4.3 years (IQR 1.5–8.4), 3 in MAD and 4 in no MAD groups required aortic valve sparing root replacement (VSRR) and 1 in MAD developed type A dissection. Over a similar imaging follow-up period [4.1 years (IQR 2.7–9.1) vs. 3.2 years (IQR 1.0–9.0), p = 0.65], compared to baseline, increase in native aortic root size was significant only in MAD (39.4 ± 4.6 mm vs. 38.1 ± 5.3 mm, p = 0.02, 19.3 ± 2.4 mm/m2 vs. 18.7 ± 2.4 mm/m2, p = 0.01) compared to those without MAD. Patients with MAD were younger at first aortic event compared to those without (26.7 ± 11.5 years vs. 45.0 ± 14.9 years, p = 0.03). MAD distance correlated with need for VSRR, r = 0.57, p = 0.02. Two patients in the MAD group developed sustained VT. No cardiac arrest or death was observed. ConclusionMAD is highly prevalent in LDS, associated with progressive aortic dilatation, and aortic events at younger age. MAD may be a marker of disease severity necessitating close surveillance.

Abstract 284: Pro-Inflammatory Adventitial Fibroblast Contribute To Aortic Aneurysms In Loeys Dietz Syndrome

Introduction: Vascular smooth muscle cell (SMC) phenotype modulation is implicated in thoracic aneurysm formation, however, the role of adventitial fibroblasts (AdvFib) in aneurysm formation remains poorly characterized. Loeys-Dietz Syndrome (LDS), caused by a spectrum of mutations in the TGF-β signaling cascade, leads to aggressive thoracic aneurysms. Given the ubiquitous nature of TGF-β signaling machinery, the exact cell type(s) responsible for initiation of LDS pathogenesis is poorly understood. Methods: We performed single cell transcriptomic characterization of aortic root and ascending aortic samples from LDS patients ((n=6 LDS (harboring TGFB2 , TGFBR1 , TGFBR2 , or SMAD3 mutation); n=2 Donor control)) as well as root/ascending aorta from a murine model of LDS ( Tgfbr2 G357W/+ ) to understand cell-state transitions and transcriptomic alterations in LDS. Results: Single cell RNA sequencing (scRNAseq) of human and mice LDS samples (in total >40,000 cells) revealed a secondary pattern of cellular activation in LDS as compared to Marfan Syndrome. Instead of SMC phenotypic modulation as seen in MFS, LDS appears to preferentially modulate adventitial fibroblasts (AdvFib) phenotype in the Tgfbr2 G357W/+ mouse model. Human LDS patient’s AdvFib turn on high levels of macrophage-recruiting pro-inflammatory cytokines CCL2 and HLA-B, with a corresponding 1.8-fold increase in LDS aortic wall macrophages compared to Donor. A more extreme pattern was observed in the Tgfbr2 G357W/+ LDS mouse model. While Tgfbr2 G357W/+ SMC are transcriptomically similar to wild type counterparts, AdvFib were activated into a pro-inflammatory state associated with increased aortic macrophage recruitment ( Ccl2 , Il6 , Vcam1, and Cxcl2 ) and fibrotic response ( Col1a1 , Col1a2 , Col3a1, and Fn1 ). A 6-fold increase in the number of aortic wall macrophages was identified in Tgfbr2 G357W/+ compared to WT. Conclusions: LDS mouse and human AdvFib undergo phenotypic alterations into a pro-inflammatory state evidenced by increased expression of numerous cytokines, macrophage recruitment, and ECM deposition. AdvFib, in addition to SMCs, are potentially another important pathological cell population in LDS aneurysm formation.

Thoracolumbar Scoliosis in Pediatric Patients With Loeys-Dietz Syndrome: A Case Series.

Background Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder that predominantly affects cardiovascular, skeletal, and craniofacial structures. Associated thoracolumbar scoliosis in LDS can be challenging to manage, though other etiologies of pediatric scoliosis have better-defined management guidelines. We examined our institutional experience regarding the treatment of pediatric patients with LDS and scoliosis. Methodology In this retrospective study, all patients seen at our pediatric tertiary care center from 2004 through 2018 with a diagnosis of LDS were reviewed, and those with radiographic diagnoses of scoliosis (full-length scoliosis X-rays) were included. Demographic, clinical, and radiographic parameters were collected, and management strategies were reported. Results A total of 39 LDS patients whose ages ranged between seven and 13 years were identified.A total of nine patients were radiographically diagnosed with scoliosis, but three patients were excluded due to incomplete medical records, leaving six patients. The median age at scoliosis diagnosis was 11.5 years, with a median follow-up of 51 months. Two patients were successfully managed with observation (average initial Cobb angle (CA): 14°, average final CA: 20.5°). Two were braced, one successfully (initial CA: 15°, final CA: 30°) and one with a progressive disease requiring surgery (initial CA: 40°, final CA: 58°). Of the two who were offered surgical correction, one underwent surgery with a durable correction of spinal deformity (CA: 33° to 19°). One patient underwent a recent correction of aortic root dilatation and was not a candidate for scoliosis surgery. Conclusions Principles of adolescent idiopathic scoliosis management such as bracing for CA of 20-50° and surgery for CA of >50° can be applied to LDS patients with good outcomes. This augments our understanding of the treatment algorithm for pediatric patients with LDS.

The relation of aortic dimensions and obesity in adults with Marfan or Loeys-Dietz syndrome.

Aortic aneurysm and aortic dissection can have a major impact on the life expectancy of Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS) patients. Although obesity can influence the development of aortic complications, evidence on whether obesity influences the development of aortic aneurysm or dissection in MFS and LDS is limited. The aim of the present study was to elucidate the relationship between aortic size and body composition, assessed by modern bioelectrical impedance analysis (BIA) in MFS/LDS-patients. In this exploratory cross-sectional study in MFS or LDS patients, enrolled between June 2020 and May 2022, 34 patients received modern BIA and magnetic resonance imaging (MRI) (n=32) or computed tomography (CT) imaging (n=2) of the entire aorta. A P value of <0.05 was considered significant. Fifty-one patients (66% female; mean age: 37.7±11.7; range, 17-68 years) with MFS or LDS were enrolled; 34 patients, 27 with MFS and 7 with LDS, underwent aortic MRI or CT scanning. The mean aortic length was 503.7±58.7 mm, and the mean thoracic aortic length and abdominal aortic length were 351.5±52.4 and 152.2±27.4 mm, respectively. The aortic bulb and the ascending aorta were measured only in the non-surgically repaired patients. Fifteen MFS (88.2%) and two LDS (40.0%) patients had an aortic aneurysm. In these, the aortic bulb tended to be larger in MFS than in LDS patients [42.6×41.9×41.2 vs. 37.8×37.4×36.8 mm; P=0.07 (-1.1; 9.1); P=0.07 (-1.2; 8.4); P=0.07 (-1.5; 7.9)]. BIA revealed mean body fat levels of 31.6%±8.7% (range, 9.5-53.5%), indicating that 18 patients (52.9%) were obese. There was a significant correlation between body fat content and thoracic aortic length (R=-0.377; P=0.02), muscle mass and total aortic length (R=0.359; P=0.03), thoracic aortic length (R=0.399; P=0.02), extracellular mass (ECM), and total aortic length (R=0.354; P=0.04), and connective tissue and aortic diameters at the aortic arch (R=0.511; P=0.002), aortic isthmus (R=0.565; P<0.001), and abdominal aorta (R=0.486; P=0.004). Older age was correlated with wider aortic arch, isthmus, and abdominal aorta. Male patients had a longer aorta. While a slender habitus is commonly known for MFS and LDS patients, our data show that many MFS and LDS patients (especially female) do not fit this phenotypic characteristic and are obese, which is associated with a more severe aortic phenotype. This topic should be included in the clinical assessment of affected MFS and LDS patients, in addition to measurement of the aortic diameters. Physicians should systematically screen MFS and LDS patients for obesity, educate them about the potential risk of resulting aortic complications, and encourage them to adopt a healthy lifestyle, that includes (mild) exercise and a balanced diet.

The spectrum of foot deformities in Loeys-Dietz syndrome.

Loeys-Dietz syndrome (LDS) is characterized by a wide spectrum of musculoskeletal manifestations, including foot deformities. The spectrum of foot deformities in LDS has not been previously characterized. Our objective was to describe the incidence and characteristics of foot deformities in LDS. We retrospectively reviewed the demographic, clinical and imaging data for patients diagnosed with LDS who were seen at our Orthopedic surgery department from 2008 to 2021. We performed descriptive analyses and compared distributions of deformities by LDS genetic mutations. Of the 120 patients studied, most presented for evaluation of foot deformities ( N = 56, 47%) and scoliosis ( N = 45; 38%). Ninety-seven patients (81%) had at least one foot deformity, and 87% of these patients had bilateral foot deformities. The most common deformities were pes planovalgus (53%) and talipes equinovarus (34%). Of patients with foot deformities, 58% presented for evaluation of the feet. Of patients with pes planovalgus, only 17% presented for evaluation of the feet. Among patients with pes planovalgus, 2% underwent surgery and 16% used orthotics compared with 76% and 42%, respectively, for patients with talipes equinovarus. We found no association between deformities and genetic mutations. Bilateral foot deformities are highly prevalent in patients with LDS and are the most common reason for presentation to orthopedic surgeons. Although pes planovalgus is the most common deformity, it rarely prompted surgical treatment. Orthopedic surgeons treating LDS patients should be aware of the unique characteristics of foot deformities in LDS.

Abstract 11748: Prophylactic Aortic Arch Replacement in Patients With Loeys-Dietz Syndrome: Surgical Outcomes and Molecular Rationale

Introduction: Loeys-Dietz syndrome (LDS) patients typically develop focal aortic root aneurysm but have substantial risk of distal aortic events (arch aneurysm and type B dissection) after root replacement. We offer prophylactic arch replacement to LDS patients of all genotypes undergoing elective valve-sparing aortic root replacement (VSARR) to prevent late aortic events. We hypothesized that non-dilated LDS aortic arch tissue demonstrates ongoing deterioration at the time of VSARR. Methods: Aortic tissue was anatomically segmented (root, ascending, arch) then examined via histology and single-cell RNA sequencing (‘scRNAseq’, n=4 patients) to comprehensively profile cellular phenotypes. Results: LDS patients (n=8, mean age 37.9 years, 87.5% male) had root aneurysm (mean 45.1 ± 8.9mm) without ascending (35.1± 7.8mm) or arch dilation (28.7 ± 2.8mm) and underwent concurrent VSARR and branched graft total arch replacement. There were no perioperative deaths or strokes and no distal aortic events or reoperations after median 1.26 years follow-up. Histologically, elastin fragmentation and collagen deposition were detectable in each aortic segment (n=4). scRNAseq identified a continuum of smooth muscle cell (SMC) phenotype modulation associated with progressively reduced contractile gene expression. Pathway analysis of 260 genes enriched during SMC modulation identified heightened integrin signaling, transforming growth factor-beta-responsiveness, cell adhesion, and extracellular matrix remodeling. Histologic confirmation using RNA probes specific for modulated SMCs (TGF-beta responsive gene SERPINE1 and glycoprotein TNFRSF11B ) identified these cells in the tunica media layer of each aortic segment, with greatest density in the root aneurysm but extending to the arch. In age-matched donor aortas, TNFRSF11B + cells were restricted to the atherosclerotic tunica intima, confirming specificity of medial SMC modulation in aneurysm. Conclusions: Total arch replacement during elective VSARR is feasible without substantial morbidity. In LDS patients with root aneurysm, matrix deterioration and SMC phenotype modulation are present in the non-dilated aortic arch, providing molecular rationale for aggressive arch replacement.

Generation and validation of an iPSC line (BBANTWi008-A) from a Loeys-Dietz Syndrome type 3 patient

Loeys-Dietz Syndrome (LDS) is an autosomal dominant connective tissue disorder. The major hallmark of LDS is thoracic aortic aneurysm and dissection (TAAD). We generated an induced pluripotent stem cell (iPSC) line of a severely affected LDS patient carrying a pathogenic SMAD3 p.Arg287Gln variant. Peripheral blood mononuclear cells were reprogrammed using non-integrating Sendai viral vectors. The autonomous pluripotency state of the resulting iPSC model was proven by the presence of pluripotency markers, trilineage differentiation potential and absence of the Sendai vector backbone. This iPSC line can be used to study and/or therapeutically target the cellular pathomechanisms of SMAD3-related LDS.

Long-term risk of arch complications in Loeys Dietz syndrome patients undergoing proximal ascending aortic replacement.

Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder. In LDS patients with normal arch morphology, whether the arch should be prophylactically replaced at the time of proximal aortic replacement remains unknown. We evaluated the risk of long-term arch complications in genetically confirmed LDS patients who underwent proximal ascending aortic replacement. We retrospectively reviewed the records of patients with LDS who have been followed at our institution between 1994 and 2020. Patients were only included if whole exome genetic testing confirmed a mutation in an LDS-causing gene (TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3). Mutations were categorized as pathogenic, benign, or of unknown significance. We collected demographic information, aortic dimensions, comorbidities, mortality, and operative course from patients' charts. Descriptive statistics and freedom from reoperation plots were generated. Of the 18 patients with a mutation in an LDS-causing gene, 15 had known pathogenic variants, two had mutations of unknown significance, and one had a benign genetic variant. For the 15 patients with confirmed pathogenic variants of LDS the median follow-up duration was 5 years (interquartile range [IQR]: 4-8). Eleven patients underwent ascending aortic replacements (AAR) ± aortic valve replacement. Two patients required an additional operation; one required arch and staged elephant trunk for a dissection 18 years post-AAR and the other patient required an isolated descending aortic replacement for dissection 5 years post-AAR. Among patients who underwent surgery, the median ascending aortic diameter at intervention was 5.0 cm (IQR: 4.3-5.3). There was no surgical or late follow-up mortality observed for any of the 18 patients in the study. LDS patients who underwent proximal aortic replacement appeared to have low long-term risk of arch complications. While our study is somewhat limited by its sample size and follow-up duration, it suggests that routine prophylactic total arch replacement may not be warranted in LDS patients with nonaneurysmal aortic arches.

Talipes Equinovarus in Loeys-Dietz Syndrome.

Loeys-Dietz syndrome (LDS) commonly presents with foot deformities, such as talipes equinovarus (TEV), also known as "clubfoot." Although much is known about the treatment of idiopathic TEV, very little is known about the treatment of TEV in LDS. Here, we summarize the clinical characteristics of patients with LDS and TEV and compare clinical and patient-reported outcomes of operative versus nonoperative treatment. We identified 47 patients with TEV from a cohort of 252 patients with LDS who presented to our academic tertiary care hospital from 2010 to 2016. A questionnaire, electronic health records, clinical photos and radiographs, and telephone calls were used to collect baseline, treatment, and outcome data. The validated disease-specific instrument was used to determine patient-reported foot/ankle functional limitations after treatment. Patients were categorized into nonoperative and operative groups, with the operative group subcategorized according to whether the posteromedial release was performed. Within our TEV cohort, bilateral TEV was present in 40 patients (85%). Thirty-seven patients underwent surgery (14 involving posteromedial release), and 10 were treated nonoperatively. The operative group had a higher incidence of posttreatment foot/ankle functional limitation (71%) than the nonoperative group (25%) ( P =0.04). The pain was the most common functional limitation (54%). The posteromedial release was associated with a higher incidence of developing hindfoot valgus compared with surgery not involving posteromedial release (43% vs. 8.7%, P =0.04) and compared with nonoperative treatment (43% vs. 0.0%, P =0.02). We found that patients with LDS have a high incidence of bilateral TEV. Operative treatment was associated with posttreatment foot/ankle functional limitations, and posteromedial release was associated with hindfoot valgus overcorrection deformity. These findings could have implications for the planning of surgery for TEV in LDS patients. Level III-retrospective comparative study.

Endovascular Iliac Artery Aneurysm Repair With Iliac Branch Endoprosthesis in Type III Loeys-Dietz Syndrome

Loeys-Dietz syndrome (LDS) type III is a rare connective tissue disorder caused by SMAD3 gene mutations that manifests with arterial tortuosity, systemic aneurysms, aortic root dilatation, and osteoarthritis. The endovascular treatment of iliac artery aneurysms with an iliac branch endoprosthesis (IBE) in LDS patients has not been described. We have presented the safety and technical feasibility of branched endovascular iliac artery aneurysm repair in a patient with a rare variant SMAD3 mutation resulting in LDS type III. A 52-year-old man with an ascending aortic root aneurysm, intercostal artery aneurysm, infrarenal abdominal aortic aneurysm, and bilateral common iliac artery (CIA) aneurysms underwent extended gene analysis. He was found to have a rare variant heterozygous autosomal dominant SMAD3 gene mutation (p.I396N) consistent with LDS type III. Because the patient was in extremis from infrarenal abdominal aortic aneurysm rupture, he underwent open replacement with a bifurcated Dacron graft and ligation of the right hypogastric artery at an unaffiliated hospital. Computed tomography angiography revealed a residual 4.7-cm left CIA aneurysm and an anatomic constraint for the IBE (proximal CIA diameter, <17 mm; Fig 1). The previously described alternative endograft aortoiliac reconstruction technique facilitated IBE repair by creation of an adequate proximal CIA landing zone with an Ovation limb (Endologix, Irving, Calif). The contralateral gate was cannulated through a left axillary cutdown. Because of a tortuous hypogastric artery, Viabahn endoprostheses (W.L. Gore & Associates, Flagstaff, Ariz) were used for hypogastric extensions, with a bridging Gore VBX stent graft. No perioperative complications occurred. At the 5-month follow-up visit, he was alive without cardiovascular morbidity. Computed tomography angiography showed branch vessel patency and sac regression, with no evidence of an endoleak or stent graft migration (Fig 2). Although branched endovascular iliac artery aneurysm repair is not the historical treatment of choice for patients with LDS type III, IBE repair can be a safe and effective minimally invasive treatment option for anatomically suitable patients.Fig 2Postoperative three-dimensional computed tomography angiogram showing patent left common iliac, external iliac, and hypogastric arteries with no evidence of endoleak or stent graft migration.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Aortic flow dynamics and stiffness in Loeys-Dietz syndrome patients: a comparison with healthy volunteers and Marfan syndrome patients.

To assess aortic flow and stiffness in patients with Loeys-Dietz syndrome (LDS) by 4D flow and cine cardiovascular magnetic resonance (CMR) and compare the results with those of healthy volunteers (HV) and Marfan syndrome (MFS) patients. Twenty-one LDS and 44 MFS patients with no previous aortic dissection or surgery and 35 HV underwent non-contrast-enhanced 4D flow CMR. In-plane rotational flow (IRF), systolic flow reversal ratio (SFRR), and aortic diameters were obtained at 20 planes from the ascending (AAo) to the proximal descending aorta (DAo). IRF and SFRR were also quantified for aortic regions (proximal and distal AAo, arch and proximal DAo). Peak-systolic wall shear stress (WSS) maps were also estimated. Aortic stiffness was quantified using pulse wave velocity (PWV) and proximal AAo longitudinal strain. Compared to HV, LDS patients had lower rotational flow at the distal AAo (P = 0.002), arch (P = 0.002), and proximal DAo (P < 0.001) even after adjustment for age, stroke volume, and local diameter. LDS patients had higher SFRR in the proximal DAo compared to both HV (P = 0.024) and MFS patients (P = 0.015), even after adjustment for age and local diameter. Axial and circumferential WSS in LDS patients were lower than in HV. AAo circumferential WSS was lower in LDS compared to MFS patients. AAo and DAo PWV and proximal AAo longitudinal strain revealed stiffer aortas in LDS patients compared to HV (P = 0.007, 0.005, and 0.029, respectively) but no differences vs. MFS patients. Greater aortic stiffness as well as impaired IRF and WSS were present in LDS patients compared to HV. Conversely, similar aortic stiffness and overlapping aortic flow features were found in Loeys-Dietz and Marfan patients.

Dysregulated TGF-β Signaling Leads to Cell-Intrinsic Changes in T cell Development that Promote Allergic Inflammation

Abstract Variants in genes in the Transforming Growth Factor Beta (TGFβ) signaling pathway are associated with allergic diseases suggesting that this cytokine may be a central player in the allergic diathesis. The role of TGFβ in preserving T cell mediated self-tolerance is well appreciated but how disruption in this pathway promotes allergic inflammation is unclear. We previously demonstrated that patients with Loeys-Dietz Syndrome (LDS), an autosomal dominant disorder caused by mutations in TGFBR1 and TGFBR2, are highly predisposed to allergic disease. LDS patients and mice harboring a knock in allele (Tgfbr1mut) of an LDS mutation known to cause severe disease in humans exhibit higher levels of total and food specific IgE. These serologic changes were associated with higher frequencies of T follicular helper (Tfh) cells and lower T follicular regulatory (Tfr) cells. Using a mixed bone marrow and fetal liver chimera model, we showed that these alterations in T cell development are cell intrinsic. Chimera models also demonstrated that the TGFβ mutation drives higher IgE production despite the presence of wildtype Tregs. Furthermore OVA specific Tgfbr1mutOTII cells were more likely to accumulate in the peyers patch and differentiate into Tfh cells in response to orally ingested OVA. These findings correlated with increased AKT/pS6 signaling downstream of TCR in Tgfbr1mut T cells, and mTOR inhibition decreased Tgfbr1mut OTII Tfh cells in response to fed ova. Additionally, RNA sequence analysis of murine Tgfbr1mut Tfh cells revealed enhanced PI3K/AKT pathway activity. These findings suggest that TGFβ signaling plays an important role in T cell development and function via the PI3K/AKT pathway that when disrupted promotes allergic inflammation.

Rotational Position of the Aortic Root is Associated with Increased Aortic Dimensions in Marfan and Loeys-Dietz Syndrome.

Progressive aortic dilation is common in Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Risk factors for progression are poorly understood. Normal variation in the aortic root (AoR) rotational position relative to the left ventricular base may impact this risk. We aimed to assess the relationship between the rotational position of the AoR and aortic dimensions in this population. Patients with a genetic diagnosis of MFS or LDS were included. AoR and ascending aorta (AAo) dimensions were measured from the first and most recent transthoracic echocardiogram. The AoR rotational angle was measured in the parasternal short-axis plane in diastole. Linear regression was used to study the correlation between AoR rotation angle and aortic dimensions. 53 MFS and 14 LDS patients were included (age 11.5 ± 5.8years at first TTE and 21.2 ± 7.2years at most recent, 68% male). The mean indexed AoR and AAo values were 2.26 ± 0.58cm/m2 and 1.64 ± 0.35cm/m2 at the first TTE and 1.98 ± 0.39cm/m2 and 1.45 ± 0.25cm/m2 at the most recent TTE, respectively. The mean AoR rotational angle was 8 ± 14°. AoR rotational angle was central (-9 to + 14°) in 42, clockwise (≥ + 15°) in 19, and counterclockwise (≤ -10°) in 6. The six outliers with counterclockwise position were excluded. There was a positive association between the AoR rotation angle and most recent TTE indexed AoR (r2 = 0.08, p = 0.02) and AAo sizes (r2 = 0.08, p = 0.02). There was no association between AoR rotational angle and rate of change in indexed AoR size (p = 0.8). There was a positive association between AoR rotation angle and rate of change in indexed AAo size (r2 = 0.10, p = 0.01). There is an association between clockwise rotational position of the AoR and increased AoR and AAo dimensions in children and young adults with MFS and LDS patients. The rotational position of the AoR may guide follow-up in these patient populations. However, this potential risk factor for dilation warrants further investigation.

Aortic Dimensions, Biophysical Properties, and Plasma Biomarkers in Children and Adults with Marfan or Loeys-Dietz Syndrome

BackgroundAortic dilation, stiffening, and dissection are common and potentially lethal complications of Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), which involve abnormal transforming growth factor beta (TGF-β) signalling. The relation of aortic dimensions, stiffness, and biomarker levels is unknown. The objective of this study was to measure aortic dimensions, stiffness, TGF-β and matrix metalloproteinase (MMP) levels, and endothelial function in patients with MFS, and to compare TGF-β levels in patients with MFS receiving different therapeutic regimens. MethodsThis was a cohort study of 40 MFS and 4 LDS patients and 87 control participants. Aortic dimension and stiffness indexes, including pulse wave velocity (PWV), were measured using echocardiography and Doppler. Total and free TGF-β and MMP blood levels were measured using Quantikine (R&D Systems, Inc, Minneapolis, MN) and Quanterix (Billerica, MA) kits. Endothelial function was measured using brachial artery flow-mediated dilation. ResultsPWV was increased in patients with MFS. There were increased MMP-2 levels in those with MFS but no increase in free or total TGF-β or MMP-9 levels compared with control participants. There was no difference in TGF-β levels between MFS patients receiving no medications, angiotensin receptor blockers, and β-blockers. PWV correlated most strongly with age. Endothelial function showed premature gradual decline in patients with MFS. ConclusionsDespite the increased PWV, monitoring aortic stiffness or TGF-β levels would not be helpful in patients with MFS. TGF-β levels were not increased and the increased MMP-2 levels suggest consideration of a different therapeutic target.

Mitral annulus disjunction is associated with adverse outcome in Marfan and Loeys-Dietz syndromes.

AimsWe aimed to assess the prevalence of mitral annulus disjunction (MAD) and to explore the association with aortic disease and mitral valve surgery in patients with Marfan syndrome (MFS) and Loeys–Dietz syndrome (LDS).Methods and resultsWe included consecutive MFS patients fulfilling Revised Ghent Criteria and LDS patients fulfilling Loeys–Dietz Revised Nosology. MAD was identified by echocardiography and was quantified as the longitudinal distance from the ventricular myocardium to the hinge point of the posterior mitral leaflet. Aortic events were defined as aortic dissection or prophylactic aortic surgery. We recorded the need of mitral valve surgery including mitral valve repair or replacement. We included 168 patients (103 with MFS and 65 with LDS). The prevalence of MAD was 41%. MAD was present in all age groups. Aortic events occurred in 112 (67%) patients (27 with dissections and 85 with prophylactic surgical interventions). Patients with MAD were younger at aortic event than those without MAD (log rank = 0.02) Patients with aortic events had greater MAD distance in posterolateral wall [8 (7–10) mm vs. 7 (6–8) mm, P = 0.04]. Mitral events occurred more frequently in patients with MAD (P < 0.001).ConclusionMAD was highly prevalent in patients with MFS and LDS. MAD was a marker of severe disease including aortic events at younger age and need of mitral valve surgery. Screening patients with MFS an LDS for MAD may provide prognostic information and may be relevant in planning surgical intervention. Detection of MAD in patients with MFS and LDS may infer closer clinical follow-up from younger age.