Citations

Background: Calcific aortic valve stenosis (CAVS) is characterized by the progressive accrual of aortic valvular calcium (AVC), resulting in impaired valvular compliance and mechanics and impaired cardiac function leading to heart failure (HF). In a phase 2 trial of 23 patients with moderate CAVS, ataciguat (ATA), a soluble guanylate cyclase activator, relative to placebo slowed the deposition of AVC, decreases in aortic valve area (AVA; by continuity equation), and increases in diastolic dysfunction and left ventricular (LV) mass. ATA may have other favorable effects on ventricular, valvular, and/or vascular pathophysiology relevant to patients with CAVS. Hypothesis: We hypothesized that slowing the rate of AVC deposition is associated with improvements in valvular compliance and in measures of cardiac structure and function. Methods: A phase 2 study randomized patients with moderate CAVS 1:1 to receive ATA 200 mg/day or placebo for up to 12 months (NCT02481258). The primary endpoint was change in AVC assessed by cardiac CT, and measures of aortic valve function and cardiac structure and function were also assessed. AVA was calculated by the Modified Gorlin (Hakki) equation to additionally assess valvular compliance. Correlations between AVC, AVA, and other measures of cardiac structure and function were assessed by exploratory linear mixed models. Results: Changes in AVC from baseline were negatively correlated with changes in AVA (slope = −0.0002 [95% CI −0.0004, 0.0001]; Figure 1), such that patients with the least AVC deposition had minimal changes in AVA. Reciprocally, changes from baseline in AVA were positively correlated with changes in cardiac output (CO; slope = 0.16 [95% CI 0.13, 0.18]; Figure 2). Treatment with ATA, compared with placebo, was associated with improvements in systolic function. Changes in AVC deposition correlated with changes in CO (slope = −0.0007 [95% CI −0.0021, 0.0008]; Figure 3), and measured improvements in CO were generally more observed in patients with less of an increase in AVC, which were more frequently observed in those treated with ATA compared with placebo. Conclusions: These data suggest that slowing the rate of AVC deposition with ATA may result in improvements in CO through improved myocardial function and valvular compliance. Larger controlled trials are needed to assess such favorable myocardial/valvular effects that may help to preserve functional capacity and slow progression to HF.

Introduction: Elevated lipoprotein(a) [Lp(a)] levels (≥30 mg/dL or ≥50 mg/dL) have been associated with increased risk of cardiovascular diseases (CVD), including myocardial infarction and aortic stenosis. However, its association with all-cause mortality (ACM) in the setting of primary prevention remains unclear, with conflicting evidence regarding the cutoff associated with increased mortality risk. Objective: To assess the association between elevated Lp(a) and risk of ACM in the context of primary prevention. Methods: In this retrospective cohort study, we included adult patients (≥18 years old) who had at least one measurement of Lp(a) at any of the three Mayo Clinic sites between 2007 and 2024, with no history of CVDs (i.e., coronary artery disease, ischemic stroke/transient ischemic attack, or peripheral arterial disease) at the time of Lp(a) measurement. Lp(a) levels were categorized based on the following percentiles: ≤50th percentile (≤11.6 mg/dL), 50th to 80th percentiles (11.6–46.6 mg/dL), 80th to 90th percentiles (46.6–75 mg/dL), 90th to 95th percentiles (75–100 mg/dL), and >95th percentile (>100 mg/dL). Survival probabilities up to 15 years were compared across Lp(a) percentile categories using the Kaplan–Meier estimator and log-rank test. Additionally, univariable and multivariable Cox regression analyses were conducted to adjust for potential CV confounders and to quantify this association. Results: A total of 42,770 patients (median age: 53 years and 54% males) were included. We found no significant difference in survival probabilities between the Lp(a) categories based on the overall log-rank test (p=0.12; Figure 1A ). In the univariable analysis, only patients with Lp(a) >95th percentile (>100 mg/dL) had a statistically significant higher risk of ACM [hazard ratio (HR): 1.37; 95%CI: 1.07–1.74; p=0.012], compared to patients with Lp(a) <50th percentile (<11.6 mg/dL). Similarly, after adjusting for potential CV risk factors, only those with Lp(a) >95th percentile (>100 mg/dL) showed a significantly higher risk of ACM (adjusted HR: 1.37; 95%CI: 1.07–1.75; p=0.012, Figure 1B ). Conclusion: In the setting of primary prevention, only very high Lp(a) levels (≥100 mg/dL) were independently associated with increased risk of ACM, suggesting that higher Lp(a) thresholds may be more relevant for identifying individuals at increased risk of ACM than the conventional ≥50 mg/dL cutoff.

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may increase thrombotic risk through immune-mediated inflammation. While venous thromboembolism is a known complication in cancer, real-world data quantifying the incidence of pulmonary embolism (PE) and deep venous thrombosis (DVT) specifically in ICI-treated patients remain limited. Methods: We conducted a retrospective cohort study of cancer patients treated with ICIs at a tertiary institution from 2011 to 2022. Electronic health records were reviewed to identify cases of PE and DVT, along with baseline characteristics and clinical outcomes at one-year follow-up. Rates of PE and DVT were compared to those reported in the literature. Time-dependent Cox regression analyses were performed to assess associations of PE and DVT with one-year all-cause mortality and heart failure (HF), defined as a new diagnosis and/or HF exacerbation/hospitalization. Results: Among patients treated with ICI, the incidence of PE and DVT was 10.6% and 8.3%, respectively. These rates are higher than those reported in several prior studies, where PE incidence in patients treated with ICI typically ranged from 3% to 6% and DVT incidence from 3% to 5%. A history of valve disease, lung cancer, and treatment with pembrolizumab or durvalumab were more frequently observed among patients with PE, whereas pembrolizumab use was most prevalent among those who developed DVT. In time-dependent Cox regression analyses, PE was significantly associated with increased one-year all-cause mortality (HR: 2.62, 95% CI: 2.12–3.23, p < 0.001) and showed a trend toward increased HF (HR: 1.63, 95% CI: 0.96–2.75, p = 0.070). Similarly, DVT was also associated with significantly higher one-year all-cause mortality (HR: 2.63, 95% CI: 2.10–3.31, p < 0.001) and a significantly greater risk of HF (HR: 1.80, 95% CI: 1.03–3.15, p = 0.040). Conclusion: In this real-world cohort study, PE and DVT were more frequent than previously recognized in ICI-treated cancer patients and were associated with significantly increased risks of all-cause mortality and heart failure. Conditions such as valve disease, lung cancer, and specific ICI therapies (e.g., pembrolizumab or durvalumab) may help identify patients at higher thrombotic risk. These findings underscore the importance of vigilant thrombotic risk assessment and may support the need for proactive monitoring or prevention strategies in high-risk patients receiving ICI therapy.

Background: A key determinant of prognosis in pulmonary hypertension (PH) is the right ventricle’s (RV) ability to adapt to increased pulmonary vascular resistance. Consequently, markers of RV-pulmonary artery (PA) coupling may improve prognostic prediction in PH. The ratio of tricuspid annular plane systolic excursion (TAPSE) to systolic PA pressure (sPAP) has been proposed as a surrogate for RV-PA coupling and a reliable prognostic marker, however, the existing data on the prognostic value of the ratio between RV longitudinal strain (RVLS) and sPAP as a surrogate for RV-PA coupling is scarce. Hypothesis: To evaluate the prognostic role of RVLS/RVSP in PH patients and to compare this novel marker with established markers of RV-PA coupling. Methods: This is a single-center study that included adult patients with PH classified as group I or IV, all of whom had undergone a transthoracic echocardiogram (TTE) within one year prior to the initiation of PH-specific treatment. Certified sonographers procured RV strain measurements using a specific software (Epsilon Imaging, Ann Arbor, MI). Receiver operating characteristic (ROC) analysis was used to determine the best cutoff for predicting all-cause mortality at one-year for RVLS/RVSP and TAPSE/RVSP. The association of RVLS/RVSP and TAPSE/RVSP with mortality at one year was assessed using the Kaplan-Meier analysis and multivariate Cox regression analysis (adjusted for REVEAL LITE 2.0 risk score). Results: A total of 160 patients were included with a median age of 67.2 (56.8, 73.7) years and 47 (29.2%) were male . ROC analysis revealed optimal cutoffs of 0.265 (AUC = 0.83) for RVLS/RVSP and 0.185 (AUC = 0.77) for TAPSE/RVSP to predict all-cause mortality at one year. One-year cumulative incidence of all-cause mortality was lower among patients with RVLS/RVSP ≥ 0.265 (0 % vs 13.7 %, p = 0.001) and patients with TAPSE/RVSP ≥ 0.185 (1.8 % vs 16.7 %, p = 0.001) (Figure 1) . In the multivariate analysis, RVLS/RVSP < 0.265 was associated with higher risk of mortality at one year (HR: 2.38, 95 % CI: 1.05 to 5.38, p = 0.036) while TAPSE/RVSP < 0.185 was not (HR: 2.01, 95 % CI: 0.93 to 4.31, p = 0.072). Conclusions: RVLS/ RVSP may be a valuable prognostic marker in PH patients and could outperform conventional TTE parameters as a surrogate for detecting RV-PA coupling.

Abstract Disclosure: A. Al Nofal: None. K. Benkhadra: None. M. Nduwimana: None. A. Mohammad: None. A. Abbas: None. Z. Wang: None. M. Murad: None. Background: Hybrid closed-loop (HCL) systems for automated insulin delivery are increasingly used in diabetes management. However, their safety and efficacy in pregnant women with pre-existing type 1 diabetes remain uncertain. Aim: To assess the safety and effectiveness of HCL systems in pregnant women with pre-existing type 1 diabetes compared to current standard of care. Methods: A comprehensive search of several databases was conducted from inception to January 3rd, 2024. Pairs of independent reviewers screened abstracts. Abstracts included by at least one reviewer were reviewed in full text by a pair of independent reviewers. The DerSimonian and Laird random effects model with the Hartung-Knapp-Sidik-Jonkman method was used to pool effect sizes across the included studies. Results: Five randomized controlled trials (RCTs) with 274 pregnant women with type I diabetes met the inclusion criteria. Our meta-analysis showed no significant difference between HCL and standard of care regarding overall time in range (TIR), time above range (TAR), and time below range (TBR). However, overnight, women using HCL showed significantly higher TIR (mean difference: 10.18%, CI 7.42-12.94%) and lower TBR (mean difference: -0.67%, CI -0.91 to -0.43%) compared to those using standard care. Additionally, there were no significant differences between HCL and standard of care in term of LGA, SGA, neonatal hypoglycemia, and maternal severe hypoglycemia or hyperglycemia. Conclusion: HCL systems for management of pre-existing type I diabetes during pregnancy are associated with similar outcomes without increased risk of complications when compared to standard of care. This is derived from limited number of RCTs with low risk of bias but significant imprecision, which warrant low confidence. Presentation: Sunday, July 13, 2025

With the first series of PRRX1 -rearranged tumors published in 2019, the spectrum of these so-called fibroblastic tumors has been expanded. Since then, several smaller case series have been published; however, our understanding of them continues to be quite limited given their rarity. We herein studied 18 additional cases, the largest series to date. Eighteen tumors present in 9 male, 8 female, and 1 nonbinary patient with a median age of 35 years (range: 11 to 70 y) and involved the neck (5), the chest region (4), thigh (3), back (1), shoulder (1), forehead (1), lower leg (1), axilla (1), and the parapharyngeal region (1). Clinical follow-up (9/18 tumors; 50%; median: 10 mo; range: 4 to 40 mo) showed consistent indolent behavior without local recurrences or distant metastases. On morphology, these tumors were characterized by well-circumscription and distinctive peripheral crescent-shaped vessels. They were composed of uniform spindle and round cells growing in short fascicles within often densely hyalinized collagen lacking significant mitotic activity, necrosis, or cytologic atypia. Immunohistochemically, about half of the tested tumors expressed focal to rarely diffuse S100 with occasional co-expression of SOX10. Interestingly, almost half of the tested cases also showed complete loss of RB expression. All but 1 tumor harbored a PRRX1::NCOA1 fusion, while 1 case harbored a novel PRRX1::EP300 fusion. We herein provide additional data on these exceptionally uncommon tumors, expand their molecular spectrum, and compare them to their close morphologic mimics to aid in accurate diagnosis and avoid confusion with potentially more aggressive neoplasms.

Abstract Objective To share findings of a quality improvement initiative to capture employment status in the electronic medical record (EMR) to mitigate the potential impact of work loss on the health of patients by utilizing the results to identify eligible individuals for resources to assist return-to-work efforts. Materials and Methods Patients self-identified employment status through a structured new social determinants of health (SDOH) question within the EMR. An electronic outreach campaign was developed to provide information via the patient portal detailing services within healthcare and the community that could benefit the patients. Results Over the course of 12 months, 2059 patients were identified from the employment SDOH question. Resources to support stay at work and return to work efforts were provided to patients through an automated electronic portal campaign with 87% of patients reading the message and 7% engaging with a healthcare return to work case manager. Discussion Loss of employment has detrimental impacts on individual and population health. Most EMRs do not capture information on employment status. Adding this simple question identified individuals with potential gaps in SDOH, and in this case allowed specific resources to be shared with patients with an illness or injury that was acutely impacting work. Conclusion Medical center decision makers and EMR programmers should consider adding employment status as a social determinant of health.