Baudhuin, Linnea M.

Background Connective tissue disorders (CTDs) such as Marfan syndrome, Loeys-Dietz syndrome, and Ehlers-Danlos syndromes are traditionally defined by vascular fragility and aortic complications. Increasing evidence, however, demonstrates that CTDs also predispose to atrial and ventricular arrhythmias, often independent of overt cardiomyopathy or severe valvular disease. Content This review integrates emerging data on the arrhythmogenic substrates of CTDs. Four mechanistic bridges are emphasized: (1) diffuse myocardial fibrosis driven by dysregulated TGF-β signaling, (2) structural valve and annular abnormalities, particularly mitral valve prolapse and mitral annular disjunction, (3) altered mechanotransduction linking extracellular matrix instability to cytoskeletal and nuclear signaling pathways, and (4) downstream ion-channel and gap-junction remodeling as secondary amplifiers. We outline the genetic architecture underlying these processes, focusing on established CTD-implicated genes in the TGF-β/SMAD pathway, valve and annulus regulators, cytoskeletal and myocyte-coupling proteins, and extracellular matrix components, while incorporating emerging CTD modifiers that expand the spectrum of arrhythmia susceptibility. Summary Recognition of CTDs as both vascular and electrical disorders reframes clinical management. Imaging markers such as mitral annular disjunction and diffuse fibrosis, together with targeted ambulatory rhythm monitoring and consideration of genetic context, may improve recognition of higher-risk phenotypes. Therapeutic strategies must balance arrhythmia control with procedural risk in fragile connective tissue substrates. Conclusions By unifying genetic, mechanistic, and clinical insights, this review provides an integrated framework for understanding arrhythmias in CTDs. It underscores the need for prospective registries and genotype-phenotype studies to refine surveillance and prevention strategies.

Background: Patients with spontaneous coronary artery dissection (SCAD) are at increased risk of cardiovascular events, including dissection in other arterial territories such as cervical arteries. Those with combined coronary and cervical arterial dissection (CACAD) may have more widespread arterial abnormalities and worse outcomes, underscoring the need for better risk stratification and personalized care. Objective: This study examined the prevalence of cervical artery dissection (CvAD) in patients diagnosed with SCAD, evaluated potential risk factors for developing CvAD, and assessed their impact on clinical outcomes, including all-cause mortality, SCAD recurrence, and stroke. The goal was to enhance risk stratification by identifying SCAD patients at increased risk for CvAD. Design: In this retrospective cohort study, patients diagnosed with SCAD between 2018 and 2024 across Mayo Clinic sites were identified using ICD-10 codes. Manual chart review confirmed CvAD diagnoses. Patients were stratified based on the presence or absence of CvAD. Chi-square and independent t-tests were used to compare risk factors and comorbidities. Univariate screening and multivariable logistic regression were used to identify predictors of CvAD. Results: Among 1380 patients with SCAD, 131 (9.5%) had CvAD. The median follow-up was 2.02 years (IQR: 1.1–5.2 years). All CvAD diagnoses were identified after the index SCAD event through systematic post-SCAD vascular imaging. The mean age was similar between groups (51.5 ± 11.3 years in CACAD vs. 50.9 ± 10.7 years in SCAD-only, p = 0.540), and the majority were female (93.9% vs. 91.9%, p = 0.529). Multivariable regression identified extremity arterial dissection (OR: 8.13, 95% CI: 3.41–19.36, p < 0.001), fibromuscular dysplasia (FMD) (OR: 7.52, 95% CI: 4.67–12.10, p < 0.001), connective tissue disorders (CTDs) (OR: 6.85, 95% CI: 2.35–19.98, p < 0.001), and anxiety (OR: 1.69, 95% CI: 1.01–2.81, p = 0.044) as significant predictors of CvAD. CvAD was a strong independent predictor of stroke (OR: 6.37, 95% CI: 2.93–13.87, p < 0.001). Mortality and SCAD recurrence did not differ significantly between groups. Conclusions: Patients with CACAD demonstrate a systemic vascular phenotype with significantly higher rates of FMD, connective tissue disease, extremity arterial dissection, and stroke. These findings highlight the importance of comprehensive vascular screening and individualized monitoring in at-risk SCAD patients.

Background The prevalence and clinical correlates of extra-aortic vascular disease in Marfan syndrome remain incompletely defined, and current surveillance strategies primarily target the thoracic aorta. Methods We conducted a multicentre retrospective cohort study of 783 patients with Marfan syndrome across three tertiary centres, with systematic chart and imaging adjudication to define aneurysm and dissection distribution. Results Extra-aortic aneurysms were identified in 32% of patients, most commonly involving the iliac, carotid and subclavian arteries. Extra-aortic dissections occurred in 5.2%. Extra-aortic aneurysms clustered strongly with markers of advanced aortic disease, including abdominal aortic aneurysm (adjusted OR 3.48), prior aortic dissection (OR 3.39) and extra-aortic dissection (OR 4.44), as well as age >40 years and male sex. Genetic confirmation status was not associated with extra-aortic aneurysm presence. Conclusions Extra-aortic vascular involvement is common in Marfan syndrome and closely linked to advanced aortic pathology. These findings support risk-stratified vascular imaging beyond the thoracic aorta in higher-risk patients.

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 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 DPYD testing can identify patients at risk for severe toxicity when a standard fluoropyrimidine antineoplastic dose is prescribed. Sequencing-based methods detect rare variants, which require classification. Methods DPYD sequencing results over a 9-year period through to 2024 were analyzed. The dataset was filtered to calculate the positive test rate for different genotyping strategies, including targeted analysis of the Association for Molecular Pathology (AMP) Tier 1 and 2 recommended alleles, and as compared to sequencing. Variant classifications based on the laboratory’s clinical protocol were compared to ClinVar classifications and designations by the Clinical Pharmacogenetics Implementation Consortium (CPIC) expert panel. Results A DPYD variant was reported in 12.79% (896/7003) of those tested, with 2.53% (170/7003) of all reports including a variant of uncertain significance. Had only AMP Tier 1 or both Tier 1 and 2 been tested, 9.30% and 9.44% of patients would have received a positive report, respectively. Among the 281 unique, non-Tier 1/Tier 2 variants encountered during sequencing, &gt;80% were not classified by the CPIC expert panel, while &gt;48% were not reported in ClinVar. Variant classifications by our laboratory and those in ClinVar were generally concordant with the CPIC expert panel, despite the lack of a standardized classification system. Conclusions While AMP Tier 1 genotyping would have identified most patients at risk for fluoropyrimidine toxicity, sequencing is more comprehensive, identifying 26% more reportable variants compared to targeted genotyping. A standard framework for pharmacogenomic variant classification could facilitate consistent variant classification and a transition from targeted genotyping to sequencing.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. METHODS: Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in APOB , LDLR , or PCSK9 . A chart review was performed to collect demographics, personal, and family cardiovascular history. RESULTS: At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 APOB , 298 LDLR , and 5 PCSK9 . Sixty-six percent were female, the mean body mass index was 27.3, with 12.3% reporting a history of diabetes. Hypertriglyceridemia (≥150 mg/dL) was present in 39.5% and reduced HDL (<50 mg/dL) was present in 56.7% of patients. 27.5% of patients were not on cholesterol-lowering medications, and only 10% of FH carriers were at goal low-density lipoprotein cholesterol levels. A history of coronary artery disease was reported in 22.4% of the cohort. Nearly 90% of these participants were newly diagnosed carriers of FH. Only 30.8% of confirmed genetic diagnoses of FH satisfied clinical (Dutch lipid clinic network) criteria for a diagnosis. CONCLUSIONS: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05212428.