bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4141304: Clinical Impact of Ventricular and Supraventricular Arrhythmia Detection with a Novel Wearable Cardioverter Defibrillator
Authors: Phukan Anisha , Syed Zain , Gustavson Laura , Li Brian , Hazarika Surovi , Syed Qarab , Chung Roy , Sharma Navneet , Pattisapu Anish , Kanj Mohamed , Chung Mina , Tanaka Esposito Christine
Published: November 2024

Background:
The wearable cardioverter defibrillator (WCD) can prevent sudden cardiac death (SCD). It also provides continuous monitoring for detection of significant cardiac arrhythmias.

Hypothesis:
Detection of ventricular and atrial arrhythmia by the WCD can significantly impact clinical decisions and outcomes.

Aims:
Report occurrence of ventricular tachycardia/fibrillation (VT/VF) and atrial fibrillation/flutter (AF/AFL) detected by the WCD and clinical consequence of these diagnoses.

Methods:
Retrospective analysis of patients prescribed the ASSURE WCD at the Cleveland Clinic. Clinical data were collected via medical chart review. Rhythm classification, of all device-detected and patient-initiated episodes displayed with 4 independent ECG channels, was manually adjudicated by a Board-Certified Electrophysiologist.

Results:
Fifty-five patients were fitted with the WCD between January 2023 and April 2024. Overall median daily use was 22 hr/day (IQR 13-24) and median duration of use was 43 days (IQR 8-79). Mean age 60.1 ± 17.6 years; 49% females; 40% ischemic cardiomyopathy; 44% nonischemic cardiomyopathy; 16% other etiology; mean Ejection Fraction (EF) 31.5 ± 6.9% pre-WCD and 38.6 ± 9.3% post-WCD.

Arrhythmia occurrence in this cohort is shown in Figure 1. Four patients (7%) had sustained VT/VF detected by the WCD, consequently all received a secondary prevention ICD. Notably, 2 patients were asymptomatic and only aware because of the device alerting of an imminent shock. Both patients showed significant recovery of EF >35% during the WCD wear period, and had sustained VT/VF not been detected by the WCD, neither would have met indication for a prophylactic ICD. Additionally, 6 patients (11%) had AF/AFL recorded by the WCD. In 3 patients AF/AFL manifested in a paroxysmal pattern and the diagnosis was new. All were at high risk for stroke with median CHADS-VaSC=4 (IQR 4-6).

Discussion:
In addition to its primary utility for preventing SCD, the WCD can detect occult yet clinically significant arrhythmia. Detection of sustained ventricular arrhythmia in asymptomatic at-risk patients resulted in secondary prevention of SCD. Documentation of AF/AFL in high-risk patients could similarly lead to impactful risk reduction.
Abstract 4141328: Exercise right heart catheterization combined with echocardiography in evaluation of subclinical pulmonary hypertension and heart failure with preserved left ventricular ejection fraction
Authors: Chetram Vishaka , Khangoora Vikramjit , Qian Xiaoxiao , Hunter Brett , Shlobin Oksana , Zhao Qiong
Published: November 2024

Introduction:
Diagnosis of exercise-induced pulmonary hypertension (EIPH) or exercise-induced heart failure with preserved left ventricular ejection fraction (E-HFpEF) is challenging due to a lack of consensus. The 2022 ESC/ERS guidelines define EIPH as mean (m) PAP/CO > 3 mmHg/L/min, and E-HFpEF as PCWP/CO > 2 mmHg/L/min, a revision of the previous criteria of mPAP ≥ 30 mmHg and PCWP ≥ 25 mmHg.

Hypothesis:
We investigated the role of exercise RHC in identifying EIPH and E-HFpEF in a group of patients with dyspnea and correlated the rest echo findings with the E-RHC results. We hypothesized that the resting echo parameters can help identify patients with EIPH and E-HFpEF using 2022 ESC/ERS definitions.

Methods:
A cohort of patients with dyspnea and normal LVEF with E-RHC data from 2016-2019 was included. Patients were categorized into Groups (g) A-E (Fig 1-T1) according to the 2018 WSPH definition of PH. Echo, hemodynamic, and clinical data were collected. The ESC/ERS 2022 guidelines were used to identify EIPH and E-HFpEF. Echo parameters were retrospectively analyzed by logistic regression analysis.

Results:
200 patients were included. The mPAP and PCWP, but not PVR, significantly increased post-exercise in all groups. Over 50% of patients in each group had evidence of at least grade I LV diastolic dysfunction on rest Echo (Fig 1). PVs/PVd was significantly lower (0.8±0.3) and E/e’ higher (15±7.9) in g-C (Post-Cap) compared to g-A (No-PH), B (Pre-Cap) and E (undifferentiated). In g-A and g-E, 46.8% and 73% demonstrated EIPH, with 87% and 100% showing a mPAP≥30 mmHg respectively. The prevalence of E-HFpEF in g-A, g-B, and g-E was 45%, 50%, and 63% respectively. Only 34%, 42%, and 56% of subjects in g-A, g-B and g-E demonstrated E-PCWP ≥ 25 mmHg. Echo parameters that predicted E-HFpEF included E and E/e’; E/e’ also predicted EIPH (Fig 1).

Conclusions:
In this study, Echo features of advanced LV diastolic dysfunction including decreased PVs/PVd and increased E/e’ were associated with post-capillary PH. Rest E/e’ and E (LV rapid inflow velocity) may predict E-HFpEF. Exercise RHC may have utility in the evaluation of patients with suspected subclinical PH and HFpEF, but larger prospective designs are warranted
Abstract 4141333: Predictors of venous thromboembolism in hospitalized patients with COVID-19
Authors: Scimeca Giovanni , Krishnathasan Darsiya , Rashedi Sina , Sato Alyssa , Lan Zhou , Hamade Nada , Bejjani Antoine , Khairani Candrika , Davies Julia , Porio Nicole , Assi Ali , Armero Andre , Tristani Anthony , Ortiz-Rios Marcos , Nauffal Victor , Almarzooq Zaid , Wei Eric , Zuluaga-Sanchez Valeria , Zarghami Mehrdad , Achanta Aditya , Jesudasen Sirus , Tiu Bruce , Merli Geno , Fanikos John , Leiva Orly , Sharma Aditya , Rizzo Samantha , Pfeferman Mariana , Morrison Ruth , Vishnevsky Alec , Hsia Judith , Nehler Mark , Welker James , Bonaca Marc , Carroll Brett , Goldhaber Samuel , Campia Umberto , Bikdeli Behnood , Piazza Gregory
Published: November 2024

Background:
COVID-19 is a multiorgan disease characterized by a prothrombotic state and increased risk of venous thromboembolism (VTE), especially in hospitalized patients. Although prior studies have attempted to identify predictors of VTE, restricted sample size and use of administrative claims data have limited such analyses. We conducted a multivariable analysis to identify predictors of VTE in hospitalized patients with COVID-19 in a multicenter patient-level registry.

Methods:
We utilized data from the CORONA-VTE Network, a US multicenter registry of 10,420 adult (≥18 years) patients with PCR-confirmed COVID-19 of whom 3,844 were hospitalized. The primary outcome was time-to-first-event for a composite of adjudicated pulmonary embolism and deep vein thrombosis (e.g. lower extremity, mesenteric, gonadal vein, etc.) during 90-day follow-up. The candidate variables were selected by a priori clinical consensus. The variables with ≥20% missing data were excluded, whereas those with missing data <20% were estimated using multiple imputation. Selected variables included prophylactic anticoagulation during hospitalization, corticosteroid therapy, female sex, baseline prescriptions of anticoagulants and statins, use of hormone replacement therapy, history of peripheral artery disease, prior VTE, and known thrombophilia. Subsequently, we conducted cox proportional hazard regression adjusted for the selected variables for each imputed dataset and pooled the estimated HRs for reporting (p<0.05 for significance).

Results:
The overall rate of VTE was 5.39%. The covariates associated with increased risk of VTE were history of VTE (HR: 1.71; 95% CI: 1.11-2.63), corticosteroid therapy (HR: 1.76; 95% CI: 1.32-2.33) and known thrombophilia (HR: 3.56; 95% CI: 1.54-8.21). The covariates associated with decreased risk of VTE were anticoagulation at baseline (HR: 0.42; 95% CI: 0.26-0.69), antecedent use of statins (HR: 0.67; 95% CI: 0.50-0.90), and prophylactic anticoagulation during hospitalization (HR: 0.52; 95% CI: 0.38-0.71).

Conclusions:
While prior VTE, corticosteroid therapy, and known thrombophilia were associated with increased risk of VTE, prescriptions of anticoagulation and statins were associated with a decreased risk.
Abstract 4141341: Association of Polygenic Risk Scores with Aortic Valve Calcium: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Whelton Seamus , YAO Jie , Clish Clary , Wood Alexis , Taylor Kent , Blaha Michael , Marrero Natalie , Thanassoulis George , Post Wendy , Guo Xiuqing , Rotter Jerome
Published: November 2024

Background:
Aortic valve calcification (AVC) is the primary underlying process leading to aortic stenosis. Whether polygenic risk scores (PRS) are associated with AVC beyond traditional atherosclerotic cardiovascular disease risk factors (ASCVD) is unknown.

Methods:
This study included 6,812 Multi-Ethnic Study of Atherosclerosis participants who had AVC measured via CT at Visit 1 and single-nucleotide polymorphism (SNP) genotype data. Using previously published PRS for coronary artery disease (CAD), coronary artery calcium (CAC), and ASCVD risk factors we calculated a weighted PRS for each participant that was standardized within each ancestry group. The cross-sectional association of the individual PRS with AVC >0 was examined using multivariable logistic regression modeling with Bonferroni correction.

Results:
The mean age was 62 years old, 53% were women, and 913 (13.4%) of participants had AVC >0 at baseline. The PRS for CAD (HR 1.17, 95% CI 1.07-1.26), SBP (HR 1.13, 95% CI 1.04-1.24), LDL-C (HR 1.16, 95% CI 1.07-1.26), and lipoprotein(a) [Lp(a)] (HR 1.11, 95% CI 1.02-1.20) were significantly associated with AVC, while the other PRS including CAC (HR 1.02, 95% CI 0.94-1.10) and CRP (HR 0.97, 95% CI 0.89-1.05) were not (Table). In sex stratified analyses, the PRS for CAD, LDL-C, and Lp(a) were significantly associated with AVC >0 for both women and men (p<0.05), while the SBP PRS for women was HR 1.14, 95% CI 0.99-1.32 and for men was HR 1.11, 95% CI 0.99-1.25.

Conclusions:
Our results further confirm the role of atherogenic lipids in the pathogenesis of AVC and suggest that SBP may also be an important risk factor for AVC, while also suggesting that inflammation may not be an independent risk factor for AVC >0. Additionally, the lack of association for the CAC PRS with AVC >0 demonstrates that significant differences exist in the calcification pathways for AVC and CAC.
Abstract 4141348: High-intensity Interval Training Improves Cardiac Function and Increases Expression of Genes Promoting Cardiomyocyte Proliferation in Myocardial-infarcted Mice
Authors: BO BING , NGUYEN THANH , Nakada Yuji , Zhang Jianyi
Published: November 2024

Background:
Previous studies in exercise-based therapies for heart failure patients have demonstrated significant improvements in symptoms and overall quality of care. However, several questions regarding exercise intensity and training modalities are yet to be answered. Also, whether and how high-intensity training (HIIT) may improve cardiac function following acute myocardial infarction (MI) has not been examined.

Research Question:
HIIT improves cardiac function in mice undergoing myocardial infarction.

Approach:
Mice were familiarized with treadmill running for five days before MI (LAD ligation); then, mice resumed HIIT following MI (MI+HIIT group). Each session of HIIT intervention in mice includes treadmill running at 90%-100% of the maximal running speed and following 30s of passive recovery, 15 sessions per day, three days per week (one exercise day followed by one rest day) for six weeks. Cardiac function was measured via ultrasound and compared among the MI+HIIT, MI mice without HIIT (MI-only), mice underwent sham operation (Sham), mice underwent HIIT without MI (HIIT-only), and control mice underwent none of these intervention (CON) groups. Cardiac cell proliferation was quantified via EdU immunohistochemistry. Cardiac Bulk-RNA sequencing data was generated to identify signaling mechanisms potentially impacted by HIIT and analyzed via the Deseq2 package and pathway enrichment analysis.

Result:
MI+MIIT mice showed significantly higher ejection fraction, fraction shortening, and cardiomyocyte EdU signal compared to the MI-only group. Pathway enrichment analysis showed that signaling pathways known for regulating cardiac regeneration, including PI3k-Akt, MAPK, Hippo, and TGFb, were significantly enriched. Also, expressions of growth factors promoting cardiomyocyte proliferation, including POSTN, FSTL1, and FST, were increased in MI+MIIT hearts.

Conclusion:
HIIT improved cardiac function in mice after MI; also, HIIT may promote regulators of heart regeneration and cardiomyocyte proliferation.
Abstract 4141358: Body weight reduction-associated and -unassociated changes in lipid profile in people with obesity, with or without T2D, treated with tirzepatide: post-hoc analysis of SURMOUNT-1 and SURMOUNT-2
Authors: Linetzky Bruno , Kyoungah See Sophia , zhang xiaotian , Stefanski Adam , Wilson Jonathan , Ruotolo Giacomo
Published: November 2024

Background:
Tirzepatide is a once weekly GIP and GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D) and obesity. This post hoc analysis evaluated the contribution of body weight reduction-associated and -unassociated effects on the lipid profile of tirzepatide-treated participants living with obesity, without and with T2D, from the SURMOUNT-1 and SURMOUNT-2 clinical trials, respectively.

Methods:
Participants treated with tirzepatide (pooled doses of 5, 10, 15 mg in SURMOUNT-1 [N=1765] and 10 and 15 mg in SURMOUNT-2 [N=587]) were included in this analysis. The estimated treatment effects and the body weight reduction-associated and -unassociated attribution on changes from baseline in lipid profile (total cholesterol, HDL-C, LDL-C, non-HDL-C, VLDL-C, and triglycerides) at 24 and 72 weeks were assessed via the SAS CAUSALMED procedure.

Results:
In SURMOUNT-1, after 24 weeks of tirzepatide treatment in participants without T2D, 69-85% of the changes in total cholesterol, HDL-C, LDL-C, and non-HDL-C, and 41-43% of the changes in VLDL-C and triglycerides occurred unassociated with body weight reduction (Table). At 72 weeks, most of the effect on the lipid profile was associated with body weight reduction. In SURMOUNT-2, after 24 weeks of tirzepatide treatment in participants with T2D, most of the changes in the lipid profile occurred unassociated with body weight reduction. At 72 weeks, changes observed in the lipid profile were predominantly associated with body weight reduction, although 43-50% of those changes also occurred unassociated with body weight reduction, except for LDL-C which was almost completely (92%) associated with body weight reduction.

Conclusions:
In this post hoc analysis from SURMOUNT-1 and SURMOUNT-2, changes in lipid profile were mostly unassociated with body weight reduction after 24 weeks of tirzepatide treatment and associated with of body weight reduction at 72 weeks. Body weight reduction-unassociated mechanisms responsible for the initial changes in lipid profile in participants with obesity treated with tirzepatide warrants further research studies.
Abstract 4141370: Artificial Intelligence for Predicting Primary Antegrade Wiring Success of Chronic Total Occlusion Crossing
Authors: Alexandrou Michaella , Rempakos Athanasios , Mutlu Deniz , Strepkos Dimitrios , Carvalho Pedro , Al-Ogaili Ahmed , Bahbah Ali , Anastasios Milkas , Tsiafoutis Ioannis , Alaswad Khaldoon , Basir Mir , Davies Rhian , Jaffer Farouc , Nicholson William , Azzalini Lorenzo , gorgulu sevket , Khatri Jaikirshan , Bangalore Sripal , Rangan Bavana , Mastrodemos Olga , Burke M Nicholas , Sandoval Yader , Brilakis Emmanouil
Published: November 2024

Background:
Incorporating artificial intelligence (AI)-based clinical decision support in the cardiac catheterization laboratory could revolutionize percutaneous coronary intervention (PCI) and interventional cardiology.

Research Questions:
To compare predictions for successful primary antegrade wiring (AW) of chronic total occlusion (CTO) lesions made by interventional cardiologists (ICs) with those from a machine learning model.

Methods:
We conducted a survey to assess the estimates of ICs regarding primary AW crossing success, on a scale of 0-100%, for 15 CTO PCIs. For the AI based prediction we used a machine learning model with an area under the curve of 0.780. The primary endpoint was the difference between AI-generated and human estimates.

Results:
A total of 130 ICs participated in the survey. Mean participant age was 51.7±10.6 years. The median difference between the AI and the human prediction was <20% for 7 cases; 20-30% for 6 cases; >30% for 2 cases. Successful AW-based crossing by an experienced CTO operator was observed in 8/15 cases. The operator predictions aligned with the real-life outcomes in 9/15 cases (60.0%), while AI correctly predicted the success/failure of primary AW CTO crossing in 11/15 cases (73.3%). Operators with more experience (>20 CTO PCIs annually) predicted higher success than less experienced operators for 5 cases. Operators who train dedicated advanced fellows predicted higher success for 6 cases and showed worse alignment with the AI prediction for 4 cases.

Conclusions:
Our study shows that, compared with physician’s estimations, a machine learning model could improve the accuracy of predictions for primary AW success and assist CTO PCI planning.
Abstract 4141378: Comparative Analysis of Hemodynamic Parameters in Heart Failure with Preserved Ejection Fraction Patients with and without Atrial Fibrillation Undergoing Exercise Right Heart Catheterization
Authors: Tajdini Masih , Tanacli Radu , Jani Vivek , Sharma Kavita
Published: November 2024

Introduction:
Atrial fibrillation (AF) is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with higher mortality. This study aims to compare hemodynamic parameters between HFpEF patients with and without AF to better understand the impact of AF on cardiac function in this population.

Method:
Patients from the Johns Hopkins HFpEF Clinic who underwent exercise right heart catheterization (July 2014 - May 2024) were included. They were categorized into two groups based on ECG findings of AF before catheterization: HFpEF-AF versus HFpEF-NonAF. Continuous variables were assessed for normal distribution using the Shapiro-Wilk test. Group differences were explored using one-way ANOVA or the Mann-Whitney U test. ANCOVA was performed to account for major confounders.

Results:
Sixty-six HFpEF patients were enrolled: 44 HFpEF-NonAF (66.7%) and 22 HFpEF-AF (33.3%). HFpEF-AF group was older (72.09 vs. 63.63 years, p < .001) and had more males (54.5% vs. 27.3%, p = 0.03). No significant differences were observed in other baseline characteristics between the two groups. More patients in the HFpEF-NonAF group reached higher stages compared to the HFpEF-AF group, indicating poorer performance in the AF group (Figure A). There were no significant differences between the groups at early stages or peak exercise regarding mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, pulmonary vascular resistance, and heart rate. However, significant differences were observed in terms of cardiac output (CO) at baseline (5.81 vs. 4.77, p = 0.035) and during exercise (8.9 vs. 7, p = 0.019), and cardiac index (CI) during peak exercise (4.14 vs. 2.90, p < 0.001) between the two groups (Figures B-F). A negative correlation between age, CO, and CI within the AF subgroup was observed. ANCOVA analysis showed HFpEF-AF patients have lower CI at peak exercise even after adjusting for age.

Discussion:
The study reveals that in HFpEF patients, those with AF exhibit significantly lower cardiac output and cardiac index during exercise compared to those without AF, despite similar pulmonary pressures. These findings underscore the importance of rhythm control strategy for AF in HFpEF patients.
Abstract 4141380: The relationships between circulating biomarkers of iron deficiency and outcomes in patients with heart failure and reduced ejection fraction: insights from DAPA-HF.
Authors: Docherty Kieran , Brennan Alice , Sukumar Shivasankar , Welsh Paul , Ponikowski Piotr , Petrie Mark , Cleland John , Solomon Scott , Jhund Pardeep , McMurray John
Published: November 2024

Background:
In patients with HFrEF, the guideline definition of iron deficiency (ID) uses both ferritin and transferrin saturation (TSAT) levels. However, observational studies and subgroup analyses of randomized controlled trials show that TSAT alone, or alternative biomarkers of ID, may better predict mortality and response to intravenous (iv) iron.

Goal:
Examine the relationships between circulating biomarkers and alternative ID definitions and outcomes in patients with HFrEF in DAPA-HF.

Methods:
Key inclusion criteria were: 1) NYHA class II-IV, 2) LVEF ≤40%, 3) elevated plasma NT-proBNP and 4) eGFR ≥30 ml/min/1.73m
2
. The primary outcome was a composite of a worsening HF event (HF hospitalization or an urgent HF visit requiring iv therapy) or cardiovascular death. Iron biomarkers were measured before randomization. The current guideline-recommended definition of ID is ferritin <100ng/mL or TSAT <20% and ferritin 100–299ng/mL. Alternative definitions examined were: iron ≤13umol/L, TSAT<20% (regardless of ferritin), and serum transferrin receptor (sTFR) >4.70mg/L (males) and >4.59mg/L (females).

Results:
Of the 4744 patients randomized, 2840 (60%) had ferritin, TSAT, iron and sTFR measured at baseline. Of these, 1228 (43%) had guideline-defined ID (374 [30%] based on ferritin <100ng/mL alone); 857 (70%) had ferritin <100ng/mL, 854 (70%) TSAT <20%, 853 (69%) iron ≤13umol/L, and 312 (25%) elevated sTFR. The lowest event rates were in iron replete patients with TSAT ≥20% and ferritin ≥100ng/mL (primary outcome=10.1/100 person-years [PY]) - Table. Event rates in iron replete patients with TSAT <20% and ferritin ≥300ng/mL were higher (17.5/100PY) and comparable to guideline-defined ID with TSAT <20% (19.3/100PY). Event rates were intermediary in guideline-defined ID patients with TSAT ≥20% and ferritin <100ng/mL (12.5/100 PY). The risk of the primary composite outcome per log-unit increase was: ferritin=HR 0.88, 95%CI 0.80-0.97; TSAT=0.75, 0.65-0.88; iron=0.79, 0.64-0.97 (and per log-unit decrease in sTFR=0.61, 0.48-0.76).

Conclusion:
Low transferrin saturation is a predictor of adverse outcomes in HFrEF, irrespective of ferritin level.
Abstract 4141390: A quality improvement intervention and academic detailing vs. academic detailing alone, a randomized quality improvement study
Authors: Sussman Jeremy , Evans Richard , Garlick Brittani , Barnes Geoffrey , Allen Arthur , Parra David , Burns Jennifer , Kurlander Jacob
Published: November 2024

Background:
Appropriate direct oral anticoagulants (DOAC) dosing could improve their safety and effectiveness. To address this, we developed an intervention to improve on-label dosing using academic detailing and a quality improvement intervention.

Methods:
This was a cluster RCT with clusters at the site level. There were 2 arms, academic detailing (AD) and AD plus Learn. Engage. Act. Process. (AD/LEAP).

Interventions:
Primary care doctors and anticoagulation pharmacists from all participating sites were invited to participate in academic detailing, a 1:1 educational and motivational coaching program, about ways to improve DOAC prescribing safely.

Intervention arm sites were also invited to participate in LEAP, a quality improvement program based on plan-do-study-act cycles.

Sites:
8 VA medical centers

Inclusion criteria:
All patients on DOACs at participating sites.

Analysis:
Generalized Estimating Equations with logit links and clusters at the facility level using aggregated proportion data. Models were weighted by the size of the denominator within each facility and longitudinal measurements were modeled with an autoregressive working correlation matrix. For difference-in-difference modeling, the 6-month pre- and post-period data were included and entered into the model as a fixed effect plus an interaction with the treatment arm.

Outcomes:
The primary outcome was the percentage of DOAC prescribing that was off-label, including under- and over-dosing for that individual and using for inappropriate indications.

Results:
Over the full length of the study, there were 34,127 patients on DOACs across the 8 sites. The percentage of prescriptions that met the primary outcome increased from 5.65 to 6.43 in the AD arm and from 5.9 to 6.43 in the AD+LEAP arm, yielding a difference-in-difference of -0.25 (95% CI -1.57- 1.06). An as-treated analysis, which dropped the two sites that did not finish their LEAP programs, also found no effect, as did sub-groups of impacts on patients whose reason for using DOACs was atrial fibrillation vs. thromboembolism.

Discussion:
A quality improvement intervention did not improve safe DOAC prescribing when added to an academic detailing intervention. We hypothesize the primary reason was insufficient engagement with the intervention.
Abstract 4141399: Chronic Moderate Alcohol Consumption In ApoE
-/-
Mice Impaires Vascular Endothelial Function Through Redox Dysregulation of Rac1
Authors: Seidel Kerstin , Ha Catherine , Johnson Rebecca , Wang Yanru , Han Jingyan
Published: November 2024

Background:
Chronic alcohol consumption is known to impair endothelial function and contribute to cardiovascular disease. However, the effects of moderate alcohol consumption on vascular function, especially in the presence of atherogenic risk factors like hypercholesterolemia, remain inconsistent and unclear.

Methods and Results:
To simulate chronic moderate and heavy drinking in hypercholesterolemic conditions, ApoE deficient (ApoE−/−) mice were fed a Lieber-DeCarli liquid diet with ethanol (2g/kg/day for moderate and 5g/kg/day for heavy drinking) or isocaloric maltose (5g/kg/day as control) for 12 weeks. In vivo flow-mediated vasodilation (FMD) of the femoral artery was assessed at 6 and 10 weeks. Both moderate and heavy alcohol consumption significantly impaired endothelium-dependent FMD, while endothelium-independent FMD increased after 10 weeks, indicated by higher FMD values in the presence of L-NAME, an eNOS inhibitor. Moderate and heavy drinking also promoted aortic endothelial permeability (measured by Evan’s blue dye infiltration) and atherosclerotic lesions at the aortic root. In aorta and endothelium-rich lung tissues, protein S-glutathionylation levels were elevated in both drinking groups, coinciding with eNOS inactivation (reduced dimer to monomer ratio), impaired Rac1 RhoGTPase activity, and increased Rac1 glutathionylation. In human aortic endothelial cells, ethanol exposure dose-dependently promoted protein S-glutathionylation and lowered glutaredoxin-1 (Grx1) levels. Moderate ethanol treatment (25mM) alone had negligible impact on eNOS and Rac1 activities but caused endothelial dysfunction under metabolic stress or Grx1 knockdown, mirroring animal study findings.

Conclusions:
This study provides evidence that moderate alcohol consumption can cause vascular endothelial dysfunction in the presence of hypercholesterolemia. The underlying mechanism involves S-glutathionylation-centered redox dysregulation of Rac1 and eNOS.
Abstract 4141401: Direct and Indirect Effects of Historic Residential Redlining on Prevalence of Cardiometabolic Diseases via Food Access
Authors: Walker Rebekah , Campbell Jennifer , Linde Sebastian , Egede Leonard
Published: November 2024

Background:
Given the importance of access to healthy food for adults at risk of cardiometabolic diseases, this study focused on investigating food access as a possible pathway between structural racism and prevalence of disease.

Methods:
Census tract level data were combined to create a final analytic dataset of 11,457 census tracts across 201 counties, within 38 states. Structural racism was defined as historic residential redlining using Home Owners’ Loan Corporation (HOLC) residential security maps from the Mapping Inequality project (score between 1=best to 4=redlined). Food access was defined using the modified retail food environment index (mRFEI) calculated as the number of healthy food retailers divided by the number of healthy and less healthy food retailers per census tract. Prevalence of disease in each census tract was based on CDC PLACES data and included prevalence of diabetes (DM), high blood pressure (HBP), coronary heart disease (CHD), and obesity. Direct and indirect relationships between redlining and each cardiometabolic disease via food access was investigated using structural equation modeling run in Stata v17, controlling for population of each census tract.

Results:
Mean prevalence of DM was 11.8%, HBP 31.9%, CHD 6.0%, and obesity 31.8%. Redlining (0.22, p<0.001) and lower food access (-0.11, p<0.001) were directly associated with higher prevalence of DM. Redlining (0.10, p<0.001) and lower food access (-0.10, p<0.001) were directly associated with higher prevalence of HBP. Redlining (0.12, p<0.001) and lower food access (-0.04, p<0.001) were directly associated with higher prevalence of CHD. Redlining (0.18, p<0.001) and lower food access (-0.12, p<0.001) were directly associated with higher prevalence of obesity. Redlining was also significantly indirectly associated with DM, HBP, CHD, and obesity via food access (-0.10, p<0.001).

Conclusions:
Structural racism measured using historical redlining is associated with higher diabetes, high blood pressure, coronary heart disease, and obesity prevalence via decreased food access. Based on these results, interventions to improve access to healthy food options at the community level may help address the impact of structural racism on the health of individuals, particularly those at risk for cardiometabolic diseases living in historically redlined neighborhoods.
Abstract 4141415: Pseudo-Fontan Physiology From Venous Lead Obstruction: A Case Report of a Rare Complication of Permanent Pacemaker Leads
Authors: Kong Nathan , zimetbaum peter
Published: November 2024

Lead related venous obstruction (LRVO) is an often underrecognized complication of pacemaker implantation. Symptoms of LRVO may include mild asymmetric upper extremity swelling to highly morbid superior vena cava (SVC) syndrome. We present an unusual case of a 54-year-old man with a history of retained pacemaker leads placed 26 years ago who presents with abdominal distention, lower extremity edema, and shortness of breath. He was found to have new onset ascites and significant pleural effusions. A liver biopsy showed hepatic fibrosis and pleural studies were consistent with chylothorax. After significant workup and diagnostic testing, it was believed that he had late complications often seen in Fontan physiology, notably hepatic fibrosis, lymphatic leakage, and protein losing enteropathy. A venogram and pressure measurements were performed which confirmed obstruction at the junction of the SVC and right atrium with elevated central filling pressures and significant flow through a markedly dilated azygous vein. A lymphangiogram suggested lymphatic leakage through the thoracic duct. An SVC stent was placed in an attempt to relieve the obstruction but the patient had progressive hemodynamic compromise leading to placement of mechanical circulatory support. Ultimately, the patient underwent surgical extraction of the retained pacemaker leads and reconstruction of the superior vena cava and right atrial junction, leading to near-resolution of his symptoms. This unusual presentation of SVC syndrome as a late complication of retained pacemaker leads highlights the potential severity of cardiac implanted electronic device lead-related complications.
Abstract 4141535: Annulo-Leaflet Mitral Ring – A Distinct Form of Valvar Endocardial Fibroelastosis
Authors: von Piechowski Magnus , Diaz-Gil Daniel , Saraci Kerstin , Rech Lavinia , Lang Nora , Marx Gerald , Carreon Chrystalle , Sanders Stephen , Emani Sitaram , Del Nido Pedro , Friehs Ingeborg
Published: November 2024

Introduction:
Treatment of congenital mitral stenosis (MS) is a major challenge due to high recurrence rate necessitating reintervention. The annulo-leaflet mitral ring (ALMR) is a unique form of congenital MS, defined as fibrous ridge/membrane located above the mitral valve (MV) and/or adherent to leaflets’ atrial surface. The underlying mechanism of ALMR formation and recurrence is unknown.

Objective:
We sought to determine recurrence of ALMR following primary resection and to establish the cellular mechanism of ALMR formation.

Methods:
A retrospective single-center cohort study of patients undergoing primary resection of an ALMR between 01/2013 and 12/2023 was conducted. The primary outcome was ALMR recurrence. Mean diastolic MV gradient and type of MV disease were determined by echocardiography. In a subset of patients with available tissue, cellular analysis was performed for endocardial fibroelastosis (EFE).

Results:
In total, 50 patients (median age 20.5 (IQR 57) months), of which 78% had additional subvalvar MV anomalies, underwent primary ALMR resection, decreasing mean MV gradient from 9.7±4.96mmHg to 4.8±3.46mmHg (p<0.001).

At discharge, 2 patients (4%) had residual ALMR, 19 (38%) MS, and 21 (42%) MV regurgitation (MR). At a median follow-up of 45 (IQR 40) months, 21 patients (42%) had MS and 14 (28%) MR, 9 (18%) underwent MV replacement, 2 (4%) experienced late deaths, and 8 (16%) were lost to follow-up. ALMR recurred in 12 patients (32%), all with additional subvalvar anomalies, and 11 (29%) underwent re-resection at a median interval of 21 (IQR 24) months. Cellular mechanism is displayed in Figure 1.

Conclusion:
Our findings show that ALMR occurs as part of a broader MV-disease complex, resulting in a high recurrence rate. We reveal for the first time that ALMR tissue originates from the endocardium through EndMT and is, hence, a distinct form of EFE. Flow disturbances due to an abnormal subvalvar MV apparatus are the likely driving force behind EFE in ALMR recurrence, which is in support of our previous findings from other complex congenital heart defects. Pharmacologically targeting the EndMT pathway might reduce disease burden for these patients and thus, could be a novel therapeutical approach.
Abstract 4141543: Exercise-induced cardiomyopathy in the absence of coronary artery disease: Clinical characteristics and outcomes.
Authors: Fazzini Luca , Hubers Scott , Cao Jenny Jia Ling , Scott Christopher , McCully Robert , Castrichini Matteo , Figueiral Marta , Mohananey Akanksha , Ghazal Rachad , Wang Min , Wang Li , Gulati Rajiv , Montisci Roberta , Pellikka Patricia , Pereira Naveen
Published: November 2024

Background:
Patients with normal resting left ventricular ejection fraction (LVEF) without either coronary artery disease (CAD) or a hypertensive response can paradoxically develop reduced LVEF during exercise stress echocardiography (ESE). The clinical phenotype and outcomes of these patients is unknown.

Hypothesis:
Patients who paradoxically develop reduced LVEF during exercise may represent a sub-phenotype of heart failure with preserved LVEF (HFpEF).

Aims:
To describe the baseline characteristics and clinical outcomes of this unique patient population.

Methods:
Among all ESE performed between January 2003 and December 2022, patients without a hypertensive response to exercise and without CAD by angiogram within 90 days of ESE, who had a resting LVEF ≥50% with a ≥5% LVEF decrease during ESE were identified. All-cause mortality, HF hospitalization, and atrial fibrillation (AF) outcomes were assessed. Kaplan-Meier and Cox regression methods were used to analyze time-to-event outcomes.

Results:
Among 213,643 stress echocardiograms performed, 134 patients met eligibility criteria (Table 1). The mean age of the population was 66±10 years, 76% were women, and 16% had AF at baseline. Mean LVEF was 58±4% at rest and 43±4% at peak stress. Stress electrocardiogram met criteria for ischemia in 14%. The 10-year all-cause mortality risk was 12.9% (95% CI 5.5-20.3) with 10 (37%) of 27 deaths due to cancer (Figure 1, Panel A). The 10-year estimated risk of HF hospitalization was 17.6% (95% CI 9.0-26.2) (Figure 1, Panel B). Among 112 patients without AF at baseline, the 10-year risk of developing AF was 23.4% (95% CI 13.4-33.4).

Conclusions:
Patients with exercise-induced reduced LVEF in the absence of obstructive CAD have a high incidence of HF hospitalizations and AF. Given the preponderance of women, risk for AF, HF hospitalizations, and cancer-related deaths, the possibility that this condition is an early sub-phenotype of HFpEF should be investigated.
Abstract 4141562: Functional evidence of regulation of the Na
V
1.5 channel through homomeric interaction of its α-subunits in the cellular membrane
Authors: Tarasov Mikhail , Radwanski Przemyslaw
Published: November 2024

Recent structural findings reveled potential interaction between Na
V
1.5 in the plasma membrane. However, functional effects of this interaction on Na
+
current (I
Na
) remain elusive.

Cell-attached patch-clamp in Chinese hamster ovary (CHO) cells stably expressing Na
V
1.5 revealed a significant increase in the ratio of persistent-to-peak I
Na
(R
persist
) in single- vs. multi-channel patches. These data suggest that reduced Na
V
1.5 surface density impacts R
persist
. Indeed, reduction of Na
V
1.5 membrane density by paclitaxel (TXL, 100 µM, 2 hours) significantly increased R
persist
of multi- but not single-channel patches relative to untreated Na
V
1.5 expressing cells (
Fig. 1
). This was further supported by a divergence in peak I
Na
predicted by a single-channel Markov model based on single-channel activity relative to experimental multi-channel recordings. To overcome the limitation of this classical model, we implemented a novel Markov model which accounts for channel interaction. Importantly, this approach not only replicated our experimental findings but also predicted a reduction of a fraction of channels in the fast inactivated state and consequently an acceleration of recovery from fast inactivation in multi-channel recordings (
Fig. 2
). Consistent with this prediction, experimental application of lidocaine (50 µM), an agent which blocks Na
V
1.5 during fast inactivation, exhibited reduced inhibitory effect in multi- vs. single-channel patches. Confirming the dependence of R
persist
on Na
V
1.5 membrane density, whole-cell patch clamp recordings in CHO cells transiently transfected with the inactivation-deficient ΔKPQ-Na
V
1.5 mutant reveled a significant negative correlation between the magnitude of whole-cell peak I
Na
density and R
persist
. Notably, increasing Na
V
1.5 cluster density with SB216763 (5 µM) in cardiomyocytes isolated from mice harboring this mutation (ΔKPQ
+/-
) significantly reduced whole-cell R
persist
relative to untreated myocytes (
Fig. 3
).

Our study suggests that Na
V
1.5 homomeric interaction may impact Na
V
1.5 kinetics and can serve as a therapeutic target for arrhythmia prevention.
Abstract 4141601: A Multimodality Education Model Improves Healthcare Professionals' Competency in Managing Cardiovascular Risk Factors in Type 2 Diabetes: A Mixed-Methods Study
Authors: Madhusudhan Divya , Okeke Oge , Bradley Sarah , Blanco Caroline , Perla Esteban , Jennings Ruby , Picou Kylie , McWeeny Patrick , Crabill CarriAnne , Pressley Alyssa , El Sayed Nuha
Published: November 2024

Introduction:
Cardiovascular disease (CVD) is the leading cause of death among people with type 2 diabetes, significantly contributing to heart attacks, strokes, and heart failure. The complex interplay between diabetes and cardiovascular risk factors necessitates ongoing medical education to advance guideline-directed care for diabetes and CVD in clinical practice. To address this need, the American Diabetes Association and American Heart Association developed a multimodality professional education model as part of the
'Know Diabetes by Heart (KDBH)
' initiative, to provide healthcare professionals with the latest insights and evidence-based practices in diabetes management.

Methods/Approach:
Introduced in a phased rollout over two years (June 2022-April 2024), this model includes 9 webinars, a comprehensive certification program, and 4 interactive gamified case study series. Utilizing a pre-and-post evaluation design grounded in the Kirkpatrick evaluation framework, we assessed the effectiveness of each education modality on key indicators of competency, confidence, and participant satisfaction. Wilcoxon signed-rank test compared pre- post intervention responses.

Results:
The study demonstrates robust engagement in a multi-faceted education model, with 2079 webinar attendees, 1,512 certification course participants, and 1,638 gamified case study participants. A sub-analysis of webinar participants (n=651) shows a statistically significant improvement in clinical competency (p<0.001, r=0.47-0.50) and confidence (p<0.001, r=0.16-0.24), with 87.4% satisfaction rate. Certification course participants (n=326) exhibit notable improvements in clinical competency (p<0.001, r=0.60-0.68) and confidence (p<0.001, r=0.55-0.61), with a satisfaction rate of 86.1%. Gamified case studies indicate a 24.3% proficiency increase. Qualitative interviews (n=19) highlight improvement in skills such as making informed treatment decisions, refining practice management workflows, enhancing patient-provider communication, and advocating for patient needs.

Conclusion:
This multimodality education model effectively engages healthcare professionals through diverse learning styles and formats, leading to significant improvements in competency and confidence in managing cardiovascular risk factors in patients with type 2 diabetes. This highlights the model's value and relevance in contemporary medical education. Future analysis will illustrate the long-term impacts of this educational approach.
Abstract 4141617: Evaluating the Cellular and Molecular Effects of Biological Sex in Porcine RV Failure
Authors: Moon Ryan , Weiblen Johannes , Kazmirczak Felipe , Prins Kurt
Published: November 2024

Introduction:
Right ventricular failure (RVF) presents a significant challenge in the management of pulmonary arterial hypertension. It is well known that there are sexually dimorphic responses in RVF as females generally exhibit superior RV function when compared to males. However, the mechanisms underlying these differences are understudied. Moreover, studies of sex differences in RV remodeling/function in large animal models are lacking. To address these two knowledge gaps, we evaluated the cellular, molecular, and functional impacts of pulmonary artery banding in male and female piglets.

Methods:
4-week-old male and female piglets underwent surgical pulmonary artery banding (PAB) to induce right ventricular dysfunction. Cardiac MRI was conducted six weeks post-banding to quantify changes in cardiac structure/function, volume, and mass. Super resolution confocal microscopy evaluated cardiomyocyte hypertrophy, transverse tubule architecture, and nuclear morphology and polyploidy. Proteomics evaluated RV mitochondrial enrichments. RV tissue was subjected to metabolomic/lipidomic analysis to probe metabolic function.

Results:
Despite having the same right ventricular ejection fraction, PAB-females had greater relative RV hypertrophy and dilation as assessed by cardiac MRI (
A-E
). Histologically, PAB-females had a nearly two-fold increase in RV cardiomyocyte cross sectional area as compared to PAB-males (
F-H
). Analysis of myocyte nuclear structure demonstrated both PAB males and females exhibited nuclear remodeling and hypertrophy, but the change in nuclear size was greater in females. Proteomic analysis revealed distinct mitochondrial signatures as fatty acid oxidation, oxidative phosphorylation, and mitochondrial ribosomal proteins were downregulated in PAB-males, but predominantly upregulated in PAB-females (
I-L
). Metabolomic/lipidomic profiling revealed divergent responses between PAB males and females as females had less accumulation of amino acids and acylcarnitines than males (
M-N
). Finally, both PAB males and females showed t-tubule derangements, but the relative change in t-tubule organization was greater in females than males (
O-P
).

Conclusion:
Male and female piglets exhibit differential cellular and molecular responses to PAB, with females having greater hypertrophic response, less metabolic/energetic derangements, and more impairment in t-tubule structure.
Abstract 4141630: Development of a Model for MEPPC Using hiPSC-HPCs and Bioprinted Purkinje Networks
Authors: Ji Pengfei , Sun Bo , Monaco Gabrielle , Heinle Jeffrey , Landstrom Andrew , Birla Ravi
Published: November 2024

Introduction:
Multifocal Ectopic Purkinje-related Premature Contractions (MEPPCs) is marked by early and frequent spontaneous membrane depolarization of the His-Purkinje cells (HPCs), which can trigger life-threatening arrhythmias and sudden death. It has been postulated that MEPPC-associated variants in
SCN5A
result in increased sodium influx leading to early depolarization and triggered arrhythmias.

Hypothesis:
Our

central hypothesis

is that MEPPC is caused by a gain-of-function in I
NAV
that leads to spontaneous HPC automaticity and triggered arrhythmogenesis originating from the CCS, which propagates into the surrounding myocardial tissue.

Aims:
The goals of this study are to develop a rigorous method to generate HPCs from human induced pluripotent stem cells (hiPSCs) and characterize he hiPSC-HPCs using IHC, qPCR and electrophysiology. A second objective of this study is to develop a method to bioengineer 3D Purkinje networks using state-of-the-art advances in laser based bioprinting.

Methods:
To generate hiPSC-HPCs, 90% of confluent hiPSCs were transitioned to GSK-3 inhibitor CHIR99021 followed by Wnt inhibitor IWP2 to generate cardiac progenitor cells. Subsequently, hiPSCs were exposed to sodium nitroprusside on day 5, which led to spontaneous beating after 10 days, followed by a change in cell morphology, transitioning to large and cylindrical cells indicative of HPCs. To generate 3D Purkinje networks, we used a commercial laser based bioprinter, the Lumen X. We optimized our bioink formulation and selected 90% PEGDA as our base polymer, supplemented with 10% GELMA.

Results:
Robust expression of both CNTN2, an HPC-specific marker, and HCN4, unique to cardiac nodal and conduction cells, was observed by IHC (
Fig. 1A
). We successfully bioprinted Purkinje networks (
Fig. 1B
) and cell viability was confirmed using a live/dead assay. Phenotype of hiPSC-HPCs within the bioprinted Purkinje networks was confirmed using CNTN2 staining (
Fig. 1C
), a marker specific for Purkinje cells.

Conclusion:
Our results demonstrate our ability to successfully reprogram hiPSCs to form HPCs and our ability to utilize these cells to bioprint human 3D Purkinje networks.