El Masry, Hicham Z

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 Marfan syndrome (MFS) is associated with progressive aortic and valvular disease requiring cardiac surgery, but contemporary data on repeat cardiac operations in adults remain limited. Methods We performed a retrospective multicentre cohort study of 783 adults with MFS evaluated across three Mayo Clinic sites. Cardiac operations, postoperative complications, echocardiographic findings and redo sternotomy events were identified by chart review. Multivariate logistic regression was used to evaluate factors associated with redo sternotomy. Results Overall, 454 patients (58.0%) underwent at least one cardiac operation, and 185 patients (23.6% of the total cohort; 41.0% of operated patients) required redo sternotomy. The most common procedures were aortic root intervention (53.4%), aortic valve intervention (39.6%), mitral valve intervention (16.1%) and tricuspid valve intervention (2.6%). Valvular abnormalities were frequent, including mitral regurgitation (51.5%), mitral valve prolapse (41.1%), tricuspid regurgitation (44.6%) and aortic regurgitation (28.5%). Major postoperative complications occurred in 15.3% of patients. On multivariate analysis, hypertension (OR 2.39, 95% CI 1.54 to 3.72), emergent initial operation (OR 3.38, 95% CI 1.97 to 5.80) and postoperative complications (OR 2.59, 95% CI 1.58 to 4.27) were independently associated with redo sternotomy, whereas repair extending beyond the aortic root was associated with lower odds (OR 0.39, 95% CI 0.29 to 0.53). Conclusion In this large multicentre cohort of adults with MFS, cardiac surgery was common, and redo sternotomy occurred frequently among operated patients. These findings provide a contemporary description of the long-term need for cardiac surgery in adults with MFS managed at tertiary referral centres.

This cross-sectional study investigates the association between lipoprotein(a) levels and risk of ventricular arrhythmias among patients with heart failure with reduced ejection fraction receiving implantable cardioverter-defibrillator therapy.

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: Transthyretin (TTR) cardiac amyloidosis is a progressive cardiomyopathy with high mortality; however, the role of implantable cardioverter-defibrillators (ICDs) in this population remains unclear. Methods: This retrospective cohort study included patients with confirmed TTR cardiac amyloidosis, with or without ICDs, from January 1, 2001, to December 31, 2024, across all three Mayo Clinic sites (Arizona, Florida, and Minnesota). Diagnosis was confirmed by endomyocardial biopsy or abnormal technetium pyrophosphate (PYP) scintigraphy. A 1:4 propensity score-matched cohort of non-ischemic cardiomyopathy (NICM) patients with ICDs served as a control group. The primary outcome was all-cause mortality, comparing transthyretin cardiac amyloidosis (TTR-CA) patients by ICD status and against matched NICM patients. Secondary analyses evaluated predictors of mortality, including the use of tafamidis and the indication for ICD (primary vs. secondary prevention). Kaplan–Meier and Cox regression analyses were used to assess predictors of survival and mortality. Results: A total of 463 patients with confirmed TTR cardiac amyloidosis were included. The median follow-up duration was 7.4 years (interquartile range (IQR): 5.3–9.2 years) for the non-ICD group and 6.8 years (IQR: 4.5–9.0 years) for the ICD group. The median age was 74.5 years (IQR: 68.0–80.0 years), and 92.9% of patients were male. Among them, 206 (44.5%) received ICDs and 257 (55.5%) did not. ICD recipients were younger (71.0 vs. 77.0 years; p = 0.001) and had higher rates of hypertension (62.6% vs. 45.6%; p = 0.001), chronic kidney disease (CKD) (62.6% vs. 44.4%; p = 0.001), and diabetes (30.1% vs. 21.8%; p = 0.043). Median left ventricular ejection fraction was lower in the ICD groups (43% vs. 54%; p = 0.007), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were higher in the ICD group (2259.0 pg/mL vs. 1503.0 pg/mL; p = 0.007). Among ICD recipients, 157 (76.2%) received the device for primary prevention, while 48 (23.3%) received the ICD for secondary prevention. Appropriate shocks were delivered in 22 patients (10.6%), primarily for ventricular tachycardia (n = 18) and ventricular fibrillation (n = 4). Inappropriate shocks occurred in six patients (3.0%), and 12 patients (5.8%) experienced device-related complications. Over 10 years of follow-up, ICD implantation did not confer a survival benefit for patients with TTR-CA compared to those without an ICD (p = 0.74). In contrast, a 1:4 propensity-matched NICM cohort with ICDs, which had a median follow-up of 7.1 years (IQR: 4.6–8.8 years), showed significantly improved survival than TTR-CA patients with ICDs (p = 0.034). Among the TTR-CA patients with ICDs, neither the use of tafamidis (p = 0.10) nor the ICD indication (primary vs. secondary prevention; p = 0.85) influenced mortality. In the Cox regression analysis, predictors of mortality in TTR-CA patients included older age (hazard ratio (HR) 1.048; p = 0.001), CKD (HR 1.637; p = 0.029), troponin T >50 ng/L (HR 1.594; p = 0.031), NT-proBNP >3000 pg/mL (HR 1.514; p = 0.050), and ejection fraction <40% (HR 1.935; p = 0.003). ICD implantation was not associated with improved survival (HR 0.932; p = 0.763). Conclusions: In conclusion, our data suggest that ICD therapy may not provide a significant overall survival benefit in older TTR-CA patients with impaired pump function; thus, prospective studies are warranted before any changes to clinical practice are considered. Key predictors of mortality included reduced ejection fraction and elevated cardiac biomarkers. Additional prospective studies are needed to clarify the role of ICDs in treatment strategies for patients with TTR-CA.