Prevalence of Periodontitis among Patients Diagnosed with Marfan Syndrome: A Cross-Sectional Study Comparing Samples of Healthy Patients

Periodontitis is an inflammatory condition caused by a bacterial plaque and characterized by progressive destruction of the tooth-supporting apparatus. Patients with Marfan syndrome (MFS) exhibit a connective tissue disorder, which can also affect oral soft and hard tissue. Thus, the aims of this cross-sectional study were to assess the association between periodontitis and MFS and secondly, to compare periodontal parameters and prevalence of disease with a control group (CG) without MFS. 152 patients (MFS=76,CG=76) were recruited to evaluate the following periodontal parameters: probing depth, gingival margin, clinical attachment level, plaque index, and bleeding on probing. The 2017 World Workshop guideline was followed for the diagnosis of the periodontal status. A multivariate analysis was performed using a multinomial logistic regression adjusted for age, gender, and smoking. The level of significance required was p < 0.05. Patients with MFS did not show a higher prevalence of periodontitis compared to the CG. However, patients with MFS did have higher values in probing depth, gingival recession, clinical attachment level, and plaque index compared to the CG patients (p < 0.05). In conclusion, although similar prevalence of periodontitis was found among the studied groups, MFS patients showed worse periodontal parameters

Fluid–structure interaction simulations outperform computational fluid dynamics in the description of thoracic aorta haemodynamics and in the differentiation of progressive dilation in Marfan syndrome patients

Abnormal fluid dynamics at the ascending aorta may be at the origin of aortic aneurysms. This study was aimed at comparing the performance of computational fluid dynamics (CFD) and fluid–structure interaction (FSI) simulations against four-dimensional (4D) flow magnetic resonance imaging (MRI) data; and to assess the capacity of advanced fluid dynamics markers to stratify aneurysm progression risk. Eight Marfan syndrome (MFS) patients, four with stable and four with dilating aneurysms of the proximal aorta, and four healthy controls were studied. FSI and CFD simulations were performed with MRI-derived geometry, inlet velocity field and Young's modulus. Flow displacement, jet angle and maximum velocity evaluated from FSI and CFD simulations were compared to 4D flow MRI data. A dimensionless parameter, the shear stress ratio (SSR), was evaluated from FSI and CFD simulations and assessed as potential correlate of aneurysm progression. FSI simulations successfully matched MRI data regarding descending to ascending aorta flow rates (R2 = 0.92) and pulse wave velocity (R2 = 0.99). Compared to CFD, FSI simulations showed significantly lower percentage errors in ascending and descending aorta in flow displacement (−46% ascending, −41% descending), jet angle (−28% ascending, −50% descending) and maximum velocity (−37% ascending, −34% descending) with respect to 4D flow MRI. FSI- but not CFD-derived SSR differentiated between stable and dilating MFS patients. Fluid dynamic simulations of the thoracic aorta require fluid–solid interaction to properly reproduce complex haemodynamics. FSI- but not CFD-derived SSR could help stratifying MFS patients.This study was funded by Ministerio de Economía y Competitividad (grant no. RTC-2016-5152-1), Fundació la Marató de TV3 (grant no. 20151330), FP7 People: Marie-Curie Actions (grant no. 267128), Instituto de Salud Carlos III (grant nos PI14/0106 and PI17/00381) and ‘la Caixa’ Foundation. M.V. was funded by CompBioMed2, grant agreement ID: 823712, funded under: H2020-EU.1.4.1.3; and SILICOFCM, grant agreement ID: 777204, funded under: H2020-EU.3.1.5.Peer ReviewedPostprint (published version

Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress

Background Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy. Methods and results In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, nuclear translocation of pNRF2 and increased 3′-nitrotyrosine levels, and collagen maturation remodeling, all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression. Conclusions Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients

Intraventricular Conundrum in a SARS-CoV-2-Positive Patient With Elevated Biomarkers of Myocardial Injury

We present a case of acute myocarditis with left ventricular dysfunction and intracavitary thrombosis in a 55-year-old man with severe acute respiratory syndrome coronavirus 2 infection (coronavirus disease 2019) who was admitted with bilateral atypical pneumonia. The patient was treated with anticoagulation and optimal heart failure therapy and had an improvement of left ventricular function and thrombus resolution. (Level of Difficulty: Intermediate.

Association between marfan syndrome and oral health status: a systematic review and meta-analysis

Background: The purpose was to identify and assess the existing scientific evidence from epidemiologic, non-experimental, observational studies of associations between Marfan's syndrome and oral diseases. Material and Methods: Electronic literature searches in MEDLINE (OVID), The Cochrane Library, Scopus and the Web of Science were conducted to identify all relevant articles. Eligibility was based on inclusion criteria, and quality assessments were conducted. The outcome variables were probing depth, gingival margin, clinical attachment level, bleeding on probing, gingival status, periodontal status, tooth mobility, furcation involvement and decayed, missing and filled teeth index. After extracting data, meta-analyses were carried out. Results: Out of 527 potentially eligible papers, 3 cross-sectional studies were included. No statistically significant differences were found in the number of sites with bleeding on probing (OR: 1.26; 95% CI: 0.47 to 3.42; P = 0.65; I2: 0%), probing depth (MD: -0.14 mm; 95% CI: -0.24 to 0.53; P = 0.46; I2: 93%), periodontal status (WMD: 0.68 points; 95% CI: -0.48 to 1.83; P = 0.25; I2: 98%) nor number of decayed, missing and filled teeth index score (MD: 1.08 points.; 95% CI: -1.27 to 3.42; P = 0.37; I2: 0%). Conclusions: Patients diagnosed with Marfan's syndrome do not seem to have worsened oral health status. Due to the high number of patients with Marfan's syndrome that have prosthetic heart valves, an adequate dental monitoring as well as a strict maintenance therapy program should be implemented

Heterogeneity of aortic disease severity in patients with Loeys-Dietz syndrome

This study aimed to determine aortic disease severity in patients with Loeys-Dietz syndrome (LDS). Thirty-three patients with LDS diagnosed and followed up at our unit were included. After reviewing all family trees, 25 deceased family members with clear clinical suspicion of having had LDS were also included. Clinical presentation, aortic dilation rate by echocardiography and age at aortic surgery, dissection or death were determined. Median aortic diameter at diagnosis was 36 mm, 43% of the patients aged >40 years had a z-score <2. Median aortic root dilation rate was 0.67 mm/year (maximum 2.0 mm/year) over a median follow-up of 2 years (IQR 1.0-4.0). In the global cohort, 31/58 patients reached a clinical endpoint; 19% death, median age: 52 years; 14% dissection, median age: 36 years; 21% aortic surgery, median age: 53 years. As expected, probands had a higher z-score (2.9 vs 1.5, p=0.019) and more often required aortic surgery (33.4% vs 18.2%, p=0.035) compared with family members. TGFBR2 carriers had a higher z-score compared with TGFBR1 carriers (3.2 vs 1.5, p=0.034) and younger age at aortic surgery (HR 4.9, 95% CI 1.5 to 123, p=0.026). Craniofacial severity index was inversely correlated with age at first event (r=-0.765, p=0.045). Although paediatric patients were not properly represented in our cohort, our patients with LDS presented a significant heterogeneity in the severity of aortic disease with large intrafamilial and interfamilial variability, aortic root aneurysm were less frequent and aortic complications less premature than previously depicted. Furthermore, aortic dilation rate was similar to that reported in Marfan syndrome and aortic root diameters appear to be larger in TGFBR2 carrier

Arrhythmia and impaired myocardial function in heritable thoracic aortic disease : an international retrospective cohort study

Background: Heritable thoracic aortic diseases (HTAD), typically entailing aortic complications, can be caused by pathogenic variants or likely pathogenic variants (PV/LPVs) in several genes, including fibrillin1 (FBN1), Actin Alpha2 (ACTA2) and genes encoding components of the transforming growth factor (TGF)-beta signaling pathway. In addition to aortic complications, non-aortic cardiac disease such as impaired myocardial function and/or arrhythmia have been increasingly reported, mainly in Marfan syndrome with underlying FBN1 PV/LPVs and are acknowledged as additional causes of morbidity and mortality. The prevalence of these manifestations in the various HTAD entities is largely unknown. Methods: This international multicentre retrospective study collected data on patients with HTAD presenting non-aortic cardiac disease. A total of 9 centers from 7 different countries participated. Patients 12 years or older carrying a PV/LPV in one of the following genes: FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3 and ACTA2 were screened. Non-aortic cardiac disease included impaired myocardial function and/or arrhythmia. Impaired myocardial function was defined as (a)symptomatic reduced ejection fraction (EF<50%). Arrhythmias included atrial fibrillation (AF), atrial flutter (AFL), ventricular tachycardia (VT), ventricular fibrillation (VF) and (aborted) sudden cardiac death (presumed arrhythmogenic) (SCD). Results: Medical records of 3219 patients with HTAD were screened (2761, 385 and 73 carrying a PV/LPV in FBN1, in a TGF-beta signaling gene and in ACTA2 respectively). Non-aortic cardiac disease was reported 142 times in 101 patients (3.1%) (age 37 [range 12-77] years, 39% female): 88 patients carrying an FBN1 PV/LPV and 13 carrying a PV/LPV in one of the TGF-beta signaling genes. Neither impaired myocardial function nor arrhythmia was reported in screened patients carrying a PV/LPV in ACTA2. Among the 142 reported non-aortic cardiac diseases, 68 (48%) were impaired myocardial function, 47 (33%) were AF/AFL and 27 (19%) were VT/VF/SCD. Among the patients with non-aortic cardiac disease, prior cardiac surgery was noted in 80% and severe valvular disease (valvular surgery or severe valvular regurgitation) in 58%, while 18% of the patients developed non-aortic cardiac disease in the absence of any of the latter. Conclusions: In patients with HTAD, arrhythmia and impaired myocardial function was reported in patients with PV/LPVs in FBN1 and in the TGF-beta signaling genes and not in patients harboring PV/LPVs in ACTA2. Though infrequent, non-aortic cardiac disease should be acknowledged as potentially severe, also occurring in young patients with no underlying significant valvular or aortic disease

Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve

Abstract Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we combined global methylation analysis with in vitro studies of flow-sensitive methylation to identify biological processes associated with BAV-aortopathy and the potential contribution of flow. Biopsies from non-dilated and dilated ascending aortas were collected from BAV (n = 21) and tricuspid aortic valve (TAV) patients (n = 23). DNA methylation and gene expression was measured in aortic intima-media tissue samples, and in EA.hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (±12 dynes/cm2) or laminar (12 dynes/cm2) flow. We show methylation changes related to epithelial-mesenchymal-transition (EMT) in the non-dilated BAV aorta, associated with oscillatory flow related to endocytosis. The results indicate that the flow-response in BAV ECs involves hypomethylation and increased expression of WNT/β-catenin genes, as opposed to an angiogenic profile in TAV ECs. The EMT-signature was exasperated in dilated BAV aortas. Aberrant EMT in BAV aortic walls could contribute to increased aneurysm susceptibility, and may be due to disturbed flow-exposure. Perturbations during the spatiotemporally related embryonic development of ascending aorta and semilunar valves can however not be excluded

Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients

Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers. Germline gain-of-function variants in this gene have been recently implicated in microcephalic dwarfism. Common clinical features of patients with TBRS include tall stature, macrocephaly, intellectual disability (ID), and a distinctive facial appearance. Differential diagnosis of TBRS comprises Sotos, Weaver, and Malan Syndromes. The majority of these disorders present other clinical features with a high clinical overlap, making necessary a molecular confirmation of the clinical diagnosis. We here describe seven new patients with variants in DNMT3A, four of them with neuropsychiatric disorders, including schizophrenia and psychotic behavior. In addition, one of the patients has developed a brain tumor in adulthood. This patient has also cerebral atrophy, aggressive behavior, ID, and abnormal facial features. Clinical evaluation of this group of patients should include a complete neuropsychiatric assessment together with psychological support in order to detect and manage abnormal behaviors such as aggressiveness, impulsivity, and attention deficit-hyperactivity disorder. TBRS should be suspected in patients with overgrowth, ID, tall stature, and macrocephaly, who also have some neuropsychiatric disorders without any genetic defects in the commonest overgrowth disorders. Molecular confirmation in these patients is mandatory.This project was supported by ISCII, FEDER funds grant: FIS-PI15/01481