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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.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Multimodality imaging plays a pivotal role in ventricular tachycardia (VT) ablation by providing critical insights into arrhythmogenic substrates and guiding procedural strategies. This updated review explores the integration of various imaging techniques, including echocardiography, cardiac magnetic resonance (CMR), multidetector computed tomography (MDCT), electroanatomical mapping (EAM), and nuclear imaging, to optimize VT ablation outcomes. Echocardiography, particularly transthoracic echocardiography (TTE), is an essential first-line tool for evaluating structural heart disease and left ventricular function. Moreover, echocardiography aids in risk stratification and procedural planning by detecting regional wall motion abnormalities and thrombus formation. Meanwhile, intracardiac echocardiography (ICE) enhances ablation precision by providing real-time catheter visualization, improving procedural success, and reducing complications such as cardiac tamponade. Nonetheless, CMR is the gold standard for myocardial tissue characterization, enabling the identification of scar burden and conduction channels critical for VT pathogenesis. Late gadolinium enhancement (LGE) facilitates preprocedural planning by localizing arrhythmogenic substrates, predicting VT recurrence risk, and informing ablation strategies. Additionally, T1- and T2-mapping techniques refine the assessment of myocardial fibrosis and inflammation, further improving patient selection and outcomes. MDCT complements CMR by offering high-resolution anatomical visualization and aids in delineating scar distribution, epicardial fat, and vascular structures, informing safe and effective ablation approaches. The integration of these imaging modalities significantly enhances VT ablation precision, reduces recurrence rates, and improves patient outcomes.

ABSTRACT Patients requiring permanent pacing after tricuspid valve intervention present challenges due to the need to cross tricuspid valve prostheses. We report three cases of successful dual coronary sinus (CS) lead implantation for biventricular pacing following a range of tricuspid interventions—surgical tricuspid annuloplasty, transcatheter edge‐to‐edge repair, and transcatheter tricuspid valve replacement. The approach avoided tricuspid valve traversal, was technically feasible and resulted in satisfactory pacing performance without procedural complications. Dual CS lead configurations were individualized based on CS anatomy and pacing characteristics. The degree of QRS narrowing achieved varied according to lead location and ventricular activation patterns, highlighting the importance of individualized lead placement strategies and device programming. Dual CS lead pacing may represent a viable alternative for biventricular pacing in selected patients with prior tricuspid valve interventions. Larger studies are needed to evaluate long‐term outcomes and define the optimal role of this approach among available pacing strategies in this patient population.

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.

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: Disparities exist in the representation of genders in cardiovascular clinical trials. Atrial fibrillation (AF) is associated with significant morbidity and mortality; however, understanding regarding the representation of women in AF-related clinical trials remains limited. Therefore, this systematic review sought to evaluate the representation of women in AF-related clinical trials. Methods: We conducted a systematic review of clinical trials using the PubMed, Scopus, and EMBASE databases from 1996 to January 1st, 2024, focusing on AF-related lifestyle interventions, pharmacological treatments, catheter ablation, and device therapies for AF. Data extraction and analysis encompassed trial characteristics, participant demographics, and funding sources. The primary outcome was the prevalence of female enrollees, quantified through participation-to-prevalence ratios (PPRs). This was estimated overall and stratified by funding source, intervention type, and enrollment region. Results: Of the 103 clinical trials involving 218,322 participants (39.5% female), the PPR ranged from 0.00 to 1.73, with an average PPR of 1.03. Meanwhile, 43% of the trials exhibited female under-representation (PPR, <0.8). University-funded trials showed higher female enrollment (mean PPR, 0.951) compared to industry/government-funded trials (mean PPR, 0.800). No differences were observed in the representation of women when comparing enrollment regions or intervention types. Conclusions: Despite advancements in AF management, gender disparities persist in AF-related clinical trial representation, particularly in industry/government-funded studies compared to university-funded trials. Thus, addressing implicit biases and enforcing sex equality guidelines are critical steps toward more inclusive cardiovascular research.

Abstract Advancements in the understanding of chronic lymphocytic leukemia (CLL) have transformed patient care, leading to the development of novel targeted therapies. Traditionally, patient fitness for treatment was based on the tolerability of chemoimmunotherapy such as fludarabine–cyclophosphamide–rituximab. As the CLL patient population is predominantly older, age has historically been a major factor in how a physician selects a patient's treatment. However, as a patient's fitness goes beyond age, the definition of patient fitness should also evolve. Here, we provide suggestions for the current best practice on assessing fitness for treating CLL. Considerations for treatment include assessment of polypharmacy, history of infections, cardiovascular and renal comorbidities, functional status, cognitive and psychological status, nutritional status, and social support. The flow of assessments can start with a typical clinical evaluation followed by geriatric, cardiovascular, and renal reviews, if needed, and include collecting a patient's full history to evaluate their risk of complications with specific CLL treatments. The severity of a patient's cardiovascular profile can range from low to high risk; for those at high risk, collaboration with a cardiologist is recommended. Geriatric assessment is advised to determine baseline frailty and resilience to tolerate treatments, to avoid inappropriate treatment or undertreating patients based on chronological age, and to align the patient's fitness status with the most optimal treatment. Continuous monitoring and assessment, regardless of therapy, are recommended. Patient preferences are also integral to this decision‐making process. Looking beyond a patient's age and basing treatment selection on their fitness is key in the new era of treatment in CLL.

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 &lt; 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 Treatment with immune-checkpoint inhibitors (ICI) may be associated with adverse cardiac events. Troponin elevation is part of the diagnostic criteria for ICI related myocarditis (ICIrM) and myocardial infarction (MI), however there is limited data for causes of troponin elevation independent of MI and ICIrM and their clinical outcomes with ICI therapy. Purpose To assess the diagnostic and prognostic value of high-sensitivity troponin T (hs-TnT) in patients treated with ICI based on different etiologies and association with cardiac events. Methods All patients treated with ICI who had hs-TnT measured at a multi-center institution from 2011 to 2022 were included. Medical records were reviewed for baseline characteristics and long-term outcomes, including cardiac death and MACE (MI, stroke, heart failure [HF]), and cause of hs-TnT elevation. Risk of cardiac events and mortality were compared for the different etiologies of hs-TnT elevation. Results Of 5,423 patients treated with ICI, 1669 had post-ICI hs-TnT measurement. Mean age was 68.7±11.3 years, 58.3% were male, with follow-up through one year from ICI first administration. Elevated hs-TnT was seen in 1136 patients, with the different causes for elevation depicted in Figure 1, panel A. ICIrM patients exhibited the highest median hs-TnT value of 364 ng/L (IQR 1096), followed by a median of 98 ng/L for MI/Type 2 ischemia, 61 ng/L for infection/sepsis, 51 ng/L for pulmonary embolus, 50 ng/L for HF and 27 ng/L for indeterminate causes, Figure 1, panel B. Additionally, median time from first ICI dose to hs-TnT elevation according to each of the diagnoses are depicted in Figure 1, panel C, with ICIrM showing the shortest median time of 44 days (IQR 74). Hs-TnT elevation in patients with ICIrM had the highest risk for cardiac death (HR 52.7, 95% CI 11.7-238.0, p&lt;0.001), followed by hs-TnT elevation due to HF (HR 15.9, 95% CI 2.9-87.0, p=0.001), MI/type 2 ischemia (HR 11.6, 95% CI 2.4-56.1, p=0.002), and infection/sepsis (HR 5.7, 95% CI 1.0-31.0, p=0.045) compared to those with no hs-TnT elevation, Figure 2, panel A. Similarly, patients with ICIrM had highest risk for MACE (HR 8.2, 95% CI 4.4-15.3, p&lt;0.001), followed by increased hs-TnT due to MI/type 2 ischemia (HR 8.1, 95% CI 5.0-13.1, p&lt;0.001), HF (HR 7.6, 95% CI 4.2-13.7, p&lt;0.001), pulmonary embolism (HR 5.1, 95% CI 2.5-10.8, p&lt;0.001), infection/sepsis (HR 4.1, 95% CI 2.4-7.0, p&lt;0.001), and indeterminate cause (HR 2.4, 95% CI 1.5-3.8, p&lt;0.001), Figure 2, panel B. Conclusions Hs-TnT measurements have prognostic value for cardiac events in cancer patients receiving ICI therapy, including in those without ICIrM. Patients with ICIrM demonstrated the highest median hs-TnT levels and the poorest outcomes, with a graded response observed; the worst prognosis was seen in patients with hs-TnT elevation due to ICIrM, followed by other causes, and those without hs-TnT elevation had the best prognosis.Figure 1 Figure 2