Osundiji, Mayowa A.

Variants in the Glucokinase Regulator ( GCKR ) gene are increasingly being detected with growing applications of genomic sequencing technologies. Despite the crucial roles of the GCKR gene in energy homeostasis, the clinical applications of GCKR variants are currently limited. We observed that a large proportion of GCKR variants that are available in gnomAD database ( https://gnomad.broadinstitute.org/ ) lacked adequate evidence of pathogenicity or benign impact. We highlight the clinical need for an improved understanding of GCKR variants by presenting 2 compelling cases of unrelated families (3 individuals in total) who harbor rare GCKR variants in the context of cornea arcus and hyperlipidemia. Our observations underscore the burgeoning need for functional as well as family segregation studies to facilitate the clinical applications of GCKR variants.

Background: Loeys–Dietz syndrome (LDS) is an autosomal dominant aortopathy characterized by aggressive aneurysm formation and arterial dissections. Pregnancy-related outcomes and timing of LDS diagnosis remain poorly characterized. Methods: Demographics, genetic, obstetric, and vascular data was collected from genetically or clinically confirmed individuals with LDS seen at the three Mayo Clinic sites from 2018 to 2025. Aneurysm progression, new aneurysm formation, and arterial dissections were recorded across all vascular beds. Vascular events were assessed during pregnancy, within 12 months postpartum, and during breastfeeding. Comparative analyses were performed between women with and without a history of pregnancy, and a single-arm descriptive analysis was conducted among patients who experienced vascular complications during the peripartum period. Continuous variables were compared using the Mann–Whitney U test, while categorical variables were analyzed using chi-square or Fisher exact tests. Results: Of 47 women with LDS, 24 had a history of pregnancy, accounting for 54 pregnancies. In the comparative analysis, age at LDS diagnosis differed significantly between women with and without a prior pregnancy: women without prior pregnancy were diagnosed at a younger age (median 23.5 years [IQR 10.8–41.0], n = 23) than those who had been pregnant (median 53.5 years [IQR 43.0–59.3], n = 24). Among pregnant women, the median age at first pregnancy was 28 years (IQR 23–34); only 4 (16.7%) knew their diagnosis before pregnancy. Of 54 pregnancies, 40 (74.1%) resulted in live birth, with 23 (57.5%) vaginal and 17 (42.5%) cesarean deliveries; preterm delivery occurred in 1 (2.5%) pregnancy, and postpartum hemorrhage in 2 (5.0%). No maternal deaths, aortic dissections, or uterine ruptures occurred during gestation or the first postpartum year. In addition, 14 women (58.3%) developed aneurysms, 6 (25.0%) experienced at least one arterial dissection, and 7 (29.2%) required surgical repair, predominantly involving the ascending and abdominal aorta. The prevalence of vascular complications did not differ significantly between groups. Conclusions: In this LDS cohort, pregnancy and the early postpartum period were not accompanied by acute aortic catastrophes, despite frequent diagnostic delay. Although women without prior pregnancy were diagnosed at a younger age, the overall burden of vascular and morphologic complications did not differ significantly by pregnancy history. These findings highlight the importance of long-term cardiovascular follow-up in women with LDS.

Abstract Background Vascular Ehlers-Danlos syndrome (VEDS) and Marfan’s syndrome are associated with cardiovascular complications, including arrhythmias. However, atrial fibrillation (AF) risk in these populations has not been frequently reported. This study assessed the AF risk in VEDS and Marfan's syndrome patients using propensity score-matched analysis from an international database. Methods The TriNetX Research Network, an international database with de-identified patient data from over 100 centers, was used to pull patients with a diagnosis of VEDS and Marfan's Syndrome. Baseline characteristics (e.g., demographics, cardiovascular comorbidities, etc.) were collected, and propensity score matching was performed to balance the cohorts. Rates of AF were collected across both cohorts, and risk analysis and Kaplan-Meier survival were used to assess outcomes. Results A total of 1,114 and 23,172 patients had VEDS and Marfan’s syndrome, respectively. After propensity score matching, each cohort included 1,091 balanced patients regarding demographics and clinical characteristics. When compared in the matched cohorts, AF incidence was lower in VEDS (4.6%) compared to Marfan’s syndrome (8.6%), with a risk difference of -0.040 (95% CI: -0.061, -0.020; z = -3.794; p < 0.001). The risk ratio was 0.532 (95% CI: 0.381, 0.742), and the odds ratio was 0.509 (95% CI: 0.358, 0.726), indicating a significantly lower risk of AF in VEDS. Kaplan-Meier analysis showed an AF survival probability of 84.23% in VEDS and 78.20% in Marfan’s syndrome (log-rank p = 0.071). The hazard ratio was 0.723 (95% CI: 0.508, 1.029), which didn’t reach statistical significance (p = 0.579). Conclusion Patients with VEDS have a significantly lower risk of developing AF compared to those with Marfan’s syndrome. However, no significant difference in AF survival probability was observed. These findings suggest significant differences in the arrhythmic burden between these connective tissue disorders, which can direct future risk stratification and management strategies.Figure 1

Abstract Background Loeys-Dietz Syndrome (LDS) is a rare connective tissue disorder characterized by mutations indifferent genes including TGFRB2, TGFBR1, TGFB2, TGFB3, and SMAD3, which significantly increase the risk of vascular abnormalities, including aneurysms and dissections. These vascular events can involve various arterial territories, although the thoracic aorta is of most concern. The current literature is limited on characterizing the aortic and extra-aortic vascular manifestation on larger cohorts of patients. Purpose This study aims at analyzing the rates of aneurysms and dissections across different vascular territories inpatients with LDS. Methods A retrospective analysis was conducted on a cohort of individuals diagnosed with LDS at our institution. Medical records were reviewed for imaging findings, including CT scans, MRIs, and ultrasounds, to identify the presence of aneurysms and dissections. Vascular territories involved included the aortic arch (ascending, and descending aorta), coronary, cerebral, carotid, vertebral, renal, splanchnic, and peripheral arteries. Results A total of 94 patients with LDS were included. 76 patients (81%) had an ascending aortic aneurysm, and 21 patients (22.5%) had an abdominal aortic aneurysm. 49 patients (52%) had aneurysms in other vascular territories, with some patients having multiple aneurysms in different regions. These included 9 patients (9.5%) with carotid, 3 patients (3.2%) with vertebral, 5 patients (5.3%) with splenic, 11 patients (11.7%) with mesenteric, 2 patients (2.1%) with renal, 15 patients (15.9%) with iliac/femoral, 6 patients (6.4%) with subclavian, 23 patients (24.5%) with cerebral, and 10 patients (10.6%) with coronary aneurysms. For aortic dissections, 13 patients (14%) had type A and 9 patients (9.5%) had type B dissections. Additionally, 20 patients had dissections in other vascular territories, with some patients experiencing dissections in multiple regions. These included 8 patients (8.5%) with carotid, 8 patients (8.5%) with vertebral, 1 patient (1.1%) with renal, 3 patients (3.2%) with iliac, 2 patients (2.1%) with coronary, and 3 patients (3.2%) with innominate artery dissections. Conclusion Aortic involvement is the most common in patients with LDS; however, these patients are also at an increased risk of developing aneurysms and dissections in various vascular territories. This highlights the importance of screening and close follow-up in these patients, potentially through whole-body imaging to identify such abnormalities. Further research is needed to identify patients at higher risk for aneurysms and dissections compared to others.

Abstract Background Loeys-Dietz Syndrome (LDS) is a connective tissue disorder caused by mutations in the TGFBR1 or TGFBR2 genes, leading to significant cardiovascular complications, particularly aortic aneurysms and dissections. Due to the progressive nature of these issues, patients often require multiple cardiac interventions throughout their lives, although this has not been comprehensively reviewed in the literature. Purpose This study aims to review trends in cardiac interventions in LDS patients to better understand the surgical course these patients go through in their lives. Methods A retrospective analysis was conducted on a cohort of individuals diagnosed with LDS at our institution. Medical records were reviewed for data on demographics and types of interventions (e.g., aortic surgeries, valve procedures) were collected. Descriptive statistics were used to analyze the frequency of interventions with comparisons made between intervention types. Results A total of 94 patients with LDS were included in the study. Among them, 69 patients (73.4%) had an ascending aortic aneurysm, and 13 patients (14%) had a type A aortic dissection. A total of 60 patients underwent aortic root replacement surgery due to aneurysm or dissection, with 10 patients (11%) having the procedure following the occurrence of a dissection. Mitral valve prolapse (MVP) was found in 34 patients (36%). Valvular interventions were performed as follows, with some patients undergoing repairs on multiple valves: 12 patients (13%) had mitral valve repair, 10 patients (11%) had tricuspid valve repair, and the aortic valve was the most intervened upon, with 37 patients (39.5%) undergoing either replacement or repair. In total, 45 patients (48%) underwent at least one valvular intervention. Additionally, 4 patients (4.5%) underwent ventricular septal defect (VSD) closure, 3 (3.5%) underwent atrial septal defect (ASD) closure, and 3 (3.5%) had both defects closed. 29 patients (31%) had a patent foramen ovale, with 17 of these patients (59%) undergoing PFO closure. Finally, 16 patients (17%) underwent coronary artery bypass grafting (CABG). Conclusion Patients with LDS often require multiple surgeries and interventions throughout their lives due to the progressive nature of the disease and its impact on the cardiovascular system. The high incidence of aortic aneurysms, dissections, and valvular abnormalities necessitates frequent surgical management, with many patients undergoing interventions such as aortic root replacement, valve repairs, and septal defect closures. Given the complex and multifaceted cardiovascular involvement in LDS, close monitoring and timely intervention are crucial for optimizing outcomes and improving quality of life for these patients.

Abstract Background Marfan syndrome (MFS) predisposes individuals to aortic dissections. Recent data suggest that atrial fibrillation and atrial flutter (AF/AFL) may increase complications and mortality in MFS patients; however, their independent role in aortic dissection remains unclear. Purpose This study aims to assess the risk of aortic dissection in MFS patients with and without AF/AFL. Methods Using the TriNetX database and ICD-10 codes, 2,447 MFS patients with AF/AFL and 20,520 without were identified. Demographics (age, sex, race, ethnicity) were evaluated, and aortic dissection outcomes were compared using risk ratios and Kaplan-Meier survival analysis. Results Patients in the AF/AFL cohort were older (mean age 60.9 ± 16.7 years vs. 38 ± 16.6 years) and had higher proportions of males (62.51% vs. 56.76%) and white patients (74.67% vs. 66.3%). Aortic dissections occurred in 13.9% of MFS patients with AF/AFL compared to 3.4% of those without, resulting in a risk difference of 10.5% (95% CI: 9.0%–11.9%) and a risk ratio of 4.04 (95% CI: 3.547–4.603). Kaplan-Meier analysis revealed significantly lower survival rates in the AF/AFL cohort (74.07% vs. 90.63%; log-rank test, p < 0.0001), with a hazard ratio of 4.232 (95% CI: 3.686–4.858). Conclusion In MFS patients, those with AF/AFL were over four times more likely to experience aortic dissection and had over four times the hazard of mortality. Screening and managing AF/AFL may be essential to preventing aortic dissections and improving outcomes in this population.Figure 1

Abstract Background Vascular Ehlers-Danlos syndrome (VEDS) and Marfan’s syndrome are associated with cardiovascular complications, including arrhythmias. However, ventricular tachycardia (VT) risk in these populations has not been frequently reported. Purpose This study aims to assess the VT risk in VEDS and Marfan's syndrome patients through an international database. Methods The TriNetX database was used to pull patients with a diagnosis of VEDS and Marfan's Syndrome. Baseline characteristics (e.g., demographics, cardiovascular comorbidities, etc.) were collected, and propensity score matching was performed to balance the cohorts. Risk analysis and Kaplan-Meier survival were used to assess outcomes. Results A total of 1,114 and 23,172 patients had VEDS and Marfan’s syndrome, respectively. After propensity score matching, each cohort included 1,091 balanced patients regarding demographics and clinical characteristics. The cohorts were balanced with a mean age of 37.7 ± 16.0 years in both groups. 68.7% and 68.8% were females in the VEDS and Marfan cohorts, the majority being White (82.2% in VEDS, 82.9% in Marfan’s). VT Incidence was lower in VEDS (0.9%) compared to Marfan’s syndrome (2.6%), with a risk difference of -0.016 (p = 0.003). Kaplan-Meier survival showed higher survival in VEDS (99.44%) vs. Marfan’s (94.04%, log-rank p = 0.002). The risk ratio for VT in VEDS was 0.357 (95% CI: 0.174, 0.732). Conclusion VEDS patients have a significantly lower VT risk compared to those with Marfan’s syndrome. These findings suggest significant differences in the arrhythmic burden between these connective tissue disorders, which can direct future risk stratification and management strategies.