Pulmonary Vein Myocardial Sleeve Length and its Association With Sex and 4q25/PITX2 Genotype.

BACKGROUND: Experimental evidence suggests genetic variation in 4q25/PITX2 modulates pulmonary vein (PV) myocardial sleeve length. Although PV sleeves are the main target of atrial fibrillation (AF) ablation, little is known about the association between different PV sleeve characteristics with ablation outcomes. OBJECTIVES: This study sought to evaluate the association between clinical and genetic (4q25) risk factors with PV sleeve length in humans, and to evaluate the association between PV sleeve length and recurrence after AF ablation. METHODS: In a prospective, observational study of patients undergoing de novo AF ablation, PV sleeve length was measured using electroanatomic voltage mapping before ablation. The sentinel 4q25 AF susceptibility single nucleotide polymorphism, rs2200733, was genotyped. The primary analysis tested the association between clinical and genetic (4q25) risk factors with PV sleeve length using a multivariable linear regression model. Covariates included age, sex, body mass index, height, and persistent AF. The association between PV sleeve length and atrial arrhythmia recurrence (>30 seconds) was tested using a multivariable Cox proportional hazards model. RESULTS: Between 2014 and 2019, 197 participants were enrolled (median age 63 years [IQR: 55 to 70 years], 133 male [67.5%]). In multivariable modeling, men were found to have PV sleeves 2.94 mm longer than women (95% CI: 0.99-4.90 mm; P < 0.001). Sixty participants (30.5%) had one 4q25 risk allele and 6 (3.1%) had 2 alleles. There was no association between 4q25 genotype and PV sleeve length. Forty-six participants (23.4%) experienced arrhythmia recurrence within 3 to 12 months, but there was no association between recurrence and PV sleeve length. CONCLUSIONS: Common genetic variation at 4q25 was not associated with PV sleeve length and PV sleeve length was not associated with ablation outcomes. Men did have longer PV sleeves than women, but more research is needed to define the potential clinical significance of this observation.

Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes.

Importance: Patients with early-onset atrial fibrillation (AF) are enriched for rare variants in cardiomyopathy and arrhythmia genes. The clinical significance of these rare variants in patients with early-onset AF is unknown. Objective: To assess the association between rare variants in cardiomyopathy and arrhythmia genes detected in patients with early-onset AF and time to death. Design, Setting, and Participants: This prospective cohort study included participants with AF diagnosed before 66 years of age who underwent whole-genome sequencing through the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data were analyzed from February 26 to September 19, 2021. Exposures: Rare variants identified in a panel of 145 genes that are included in cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. Main Outcomes and Measures: The primary study outcome was time to death and was adjudicated from medical records and the National Death Index. Multivariable Cox proportional hazards regression was used to evaluate the association of disease-associated variants with risk of death after adjustment for age at AF diagnosis, sex, race, body mass index, left ventricular ejection fraction, and an interaction term of age at AF diagnosis and disease-associated variant status. Results: Among 1293 participants (934 [72%] male; median age at enrollment, 56.0 years; IQR, 48.0-61.0 years), disease-associated (pathogenic or likely pathogenic) rare variants were found in 131 (10%). During a median follow-up of 9.9 years (IQR, 6.9-13.2 years), 219 participants (17%) died. In univariable analysis, disease-associated variants were associated with an increased risk of mortality (hazard ratio, [HR], 1.5; 95% CI, 1.0-2.1; P = .05); the association remained significant in multivariable modeling when adjusted for age at AF diagnosis, sex, race, body mass index, left ventricular ejection fraction, and an interaction term between disease-associated variant status and age at AF diagnosis. The interaction demonstrated that disease-associated variants were associated with a significantly higher risk of mortality compared with no disease-associated variant when AF was diagnosed at a younger age (P = .008 for interaction). Higher body mass index (per IQR: HR, 1.4; 95% CI, 1.2-1.6; P < .001) and lower left ventricular ejection fraction (per IQR: HR, 0.8; 95% CI, 0.7-0.8; P < .001) were associated with higher mortality risk. There were 73 cardiomyopathy-related deaths, 40 sudden deaths, and 10 stroke-related deaths. Mortality among patients with the most prevalent genes with disease-associated variants was 26% (10 of 38 patients) for TTN, 33% (6 of 18) for MYH7, 22% (2 of 9) for LMNA, 0% (0 of 10) for MYH6, and 0% (0 of 8) for KCNQ1. Conclusions and Relevance: The findings suggest that rare variants in cardiomyopathy and arrhythmia genes may be associated with increased risk of mortality among patients with early-onset AF, especially those diagnosed at a younger age. Genetic testing may provide important prognostic information for patients with early-onset AF.

Chest Pain in a Psychiatric Patient Due to Clozapine-Induced Myopericarditis.

Drug-induced myocarditis is a rare, but underrecognized complication of clozapine therapy for schizophrenia. We present a case of clozapine-induced myocarditis with recovery of cardiac function after drug cessation and summarize the literature to highlight the variable presentation of this condition.

Defining Prolonged Dwell Time: When Are Advanced Inferior Vena Cava Filter Retrieval Techniques Necessary? An Analysis in 762 Procedures.

BACKGROUND: Despite growth in placement of retrievable inferior vena cava filters, retrieval rates remain low. Filters with extended implantation times present a challenge to retrieval, where standard techniques often fail. The development of advanced retrieval techniques has positively impacted retrieval of retrievable inferior vena cava filters with prolonged dwell times; however, there is no precise definition of the time point when advanced techniques become necessary. We aim to define prolonged retrievable inferior vena cava filters dwell time by determining the inflection point when the risk of standard retrieval technique failure increases significantly, necessitating advanced retrieval techniques to maintain overall technical success of retrieval. METHODS AND RESULTS: From January 2009 to April 2015, 762 retrieval procedures were identified from a prospectively acquired database. We assessed patient age/sex, filter dwell time, procedural technical success, the use of advanced techniques, and procedure-related adverse events. Overall retrieval success rate was 98% (n=745). When standard retrieval techniques failed, advanced techniques were used; this was necessary 18% of the time (n=138). Logistic regression identified that dwell time was the only risk factor for failure of standard retrieval technique (odds ratio, 1.08; 95% confidence interval, 1.05-1.10; P<0.001). Spline function regression analysis demonstrated that if dwell time exceeded 7 months, the risk of standard technique failure was 40.9%. Adverse events occurred at a rate of 2% (n=18; 15 minor and 3 major). CONCLUSIONS: The necessity of advanced techniques to maintain technical success of retrieval increases with dwell time. Patients with retrievable inferior vena cava filters in place beyond 7 months may benefit from referral to centers with expertise in advanced filter retrieval.

Retrieval of Inferior Vena Cava Filters: Technical Considerations.

Placement of retrievable inferior vena cava filters has seen rapid growth since their introduction into clinical practice. When retrieved, these devices offer the notional benefit of temporary protection from pulmonary embolism related to lower extremity deep venous thrombosis, and mitigation of filter-related deep venous thrombosis. When promptly removed after the indication for mechanical prophylaxis is no longer present, standard endovascular retrieval techniques are frequently successful. However, the majority of these devices are left in place for extended periods of time, which has been associated with greater device-related complications when left in situ, and failure of standard techniques when retrieval is attempted. The development of advanced retrieval techniques has had a positive impact on retrieval of these embedded devices. In this article, technical considerations in the retrieval of such devices, with an emphasis on advanced techniques to facilitate retrieval of embedded devices, are discussed.

Systemic iron chelation results in limited functional and histological recovery after traumatic spinal cord injury in rats.

Excess iron accumulation within the spinal cord is thought to exacerbate tissue damage and limit functional recovery after traumatic spinal cord injury (SCI). An optimal treatment to reverse or prevent damage would be to deliver an iron chelator systemically. Thus, we tested oral delivery of deferasirox (Exjade) in multiple studies using a rat model of mid-thoracic spinal contusion. Female Sprague-Dawley rats received a moderate contusion at vertebral level T8 and were given daily deferasirox for the first 7 or 14 days post-injury. The first two studies showed modest improvements in hindlimb function with limited improvement in tissue sparing. Two subsequent experiments to assess chronic functional changes and test longer-duration treatments failed to produce significant improvements. Testing a 2-fold higher deferasirox dose resulted in toxic side effects. To verify iron chelation treatment was effective, hepatic iron levels were measured which revealed that deferasirox robustly and significantly reduced systemic iron levels. Overall, this study suggests that oral iron chelation with deferasirox may lead to small but significant improvements in locomotor recovery or tissue sparing. However, given the lack of robust beneficial effects combined with potentially detrimental side effects such as exacerbated systemic anemia, oral administration of iron chelators may not be ideal for minimizing intraspinal iron-mediated pathology after SCI.