Shamoun, Fadi

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.

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.

Introduction: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder caused by pathogenic variants in the COL3A1 gene, often leading to arterial, intestinal, and uterine rupture. While vascular complications are well-documented, the prevalence and characteristics of cardiac arrhythmias in this population remain underexplored. Aim: To assess the prevalence of arrhythmias and conduction abnormalities in patients with confirmed vEDS. Methods: A retrospective cohort study was conducted across all three Mayo Clinic sites. Patients with vEDS were initially identified using an electronic data extraction tool. Each case was subsequently confirmed through detailed chart review. Additional reviews were performed to assess the prevalence of heart blocks and both atrial and ventricular arrhythmias. Statistical analysis was conducted using SPSS to determine the prevalence of each arrhythmia type. Results: A total of 132 patients with confirmed vEDS were included in the study. The mean age was 45.7 ± 13 years. The cohort was predominantly white (93.7%), with 47 males (35.6%) and 85 females (64.4%). Atrial arrhythmias were identified in 15 patients (11.4%), including atrial fibrillation in 14 (10.6%) and atrial flutter in 8 (6.1%). Supraventricular tachycardia (SVT) was observed in 15 patients (11.4%). Conduction abnormalities included first-degree AV block in 8 (6.1%), second-degree AV block in 3 (2.3%), left bundle branch block in 8 (6.1%), and right bundle branch block in 15 (11.4%) patients. Ventricular arrhythmias were observed in 6 patients (4.5%) with sustained ventricular tachycardia, 6 (4.5%) with non-sustained ventricular tachycardia, and 7 (5.3%) with ventricular fibrillation. Postural orthostatic tachycardia syndrome (POTS) or orthostatic hypotension was documented in 18 patients (13.6%). Conclusion: Although arrhythmias are not the most common manifestation of vEDS, their prevalence in this cohort is notably higher than in the general population and tends to occur at a younger age. These findings support the consideration of routine screening for atrial and ventricular arrhythmias in patients with vEDS as part of their long-term cardiovascular management.

Background: Loeys-Dietz syndrome (LDS) and vascular Ehlers-Danlos syndrome (vEDS) are rare connective tissue disorders characterized by arterial fragility and early-onset vascular events. Stroke risk is elevated in both conditions, but data on stroke subtypes and anticoagulation use remain limited. Understanding the relationship between stroke mechanisms, arrhythmias, and antithrombotic therapy is crucial in these genetically vulnerable populations. Aim: To assess the prevalence and subtypes of stroke in patients with LDS and vEDS. Methods: A retrospective chart review was conducted across three Mayo Clinic sites. Patients with LDS and vEDS were identified using an electronic data extraction tool, followed by manual chart review for diagnostic confirmation. Stroke subtypes, ischemic, dissection-related, and hemorrhagic, were classified based on imaging findings and clinical documentation. Data on atrial arrhythmias, valve replacement status, and anticoagulation use (including warfarin and apixaban) were systematically collected and analyzed. Results: In the LDS cohort, 12 of 94 patients (12.8%) experienced a stroke: 8 ischemic (8.5%), 3 dissection-related (3.2%), and 1 hemorrhagic (1.1%). Atrial fibrillation or flutter was present in 7 patients (58.3%), 6 of whom had ischemic strokes. Among the stroke patients, 9 (75%) had prosthetic valves, 6 mechanical and 3 bioprosthetic, and 4 (33.3%) were on warfarin at the time of the event. In the vEDS cohort, 22 of 132 patients (16.7%) had strokes: 13 ischemic (9.8%) and 9 dissection-related (6.8%). No hemorrhagic strokes were observed. Atrial fibrillation or flutter was documented in 12 patients (54.5%), with 10 experiencing ischemic and 2 dissection-related strokes. Of these, 5 (22.7%) were on apixaban, 3 (13.6%) on warfarin, and 4 (18.2%) were not anticoagulated. None of the vEDS stroke patients had mechanical valves. Conclusion: Ischemic stroke is the most frequent cerebrovascular event in both LDS and vEDS, but dissection-related strokes are more common in vEDS. Atrial arrhythmias often precede ischemic events, yet anticoagulation use varies widely. One-third of dissection-related strokes occurred despite antithrombotic therapy, raising concerns about current management strategies. These findings support the need for syndrome-specific guidelines for stroke prevention, arrhythmia management, and anticoagulation in LDS and vEDS patients.

Thoracic aortic aneurysm and dissection (TAAD) encompasses a clinically heterogeneous group of diseases characterized by high morbidity and mortality. Genetic studies over the past two decades have significantly expanded our understanding of the molecular landscape underlying heritable TAAD, revealing contributions from multiple interconnected biological pathways. This review systematically summarizes more than 75 genes implicated in TAAD pathogenesis, categorizing them according to major mechanistic roles including TGF-β signaling, extracellular matrix remodeling, smooth muscle cell contractility and cytoskeletal regulation, cell–matrix and cell–cell adhesion, metabolic processes, ion transport, and transcriptional regulation. Special emphasis is placed on emerging genes with variable or overlapping clinical phenotypes, dual-mechanism candidates, and their implications for personalized clinical management, including surveillance and surgical intervention thresholds. The integration of molecular insights into clinical practice, along with cautious consideration of genes of uncertain significance, promises to enhance diagnostic precision and risk stratification in individuals and families affected by heritable aortic disease.