bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4118380: In-Hospital Outcome of Acute Heart Failure in Patients with Active Chronic Lymphocytic Leukemia
Authors: Olanisa Olawale , Bolaji Olayiwola , Nzeako Tochukwu , Oriaifo Osejie
Published: November 2024

Introduction:
Chronic lymphocytic leukemia (CLL) is prevalent among adults in Western countries, posing a significant health challenge due to its incurable nature and associated complications. Among these, cardiovascular disease, particularly heart failure (HF), has emerged as a major concern. Despite growing recognition, understanding of acute HF's epidemiology, outcomes, and risk factors in CLL patients remains limited. To address these gaps, we conducted a large-scale study using the National Inpatient Sample (NIS) database, aiming to examine acute HF prevalence, trends, outcomes, and predictors among CLL hospitalizations.

Methods:
We employed a retrospective cohort design utilizing NIS data from 2016 to 2021. CLL hospitalizations with and without acute HF were identified using ICD-10 codes. Our analysis included demographic characteristics, in-hospital outcomes, and multivariable logistic regression to identify predictors of outcomes. Propensity score matching was performed to mitigate confounding factors.

Results:
Among 423,829 CLL hospitalizations, 27.8% presented with acute HF. Patients with acute HF were older and had higher rates of comorbidities. While acute HF prevalence remained stable, in-hospital mortality increased over time, contrasting with stable rates among patients without acute HF. Acute HF was associated with higher mortality, cardiogenic shock, cardiac arrest, and major adverse cardiovascular events. Propensity score-matched analysis confirmed these associations.

Discussion:
Our study highlights acute HF as a common complication in CLL hospitalizations, linked with worse outcomes. The multifactorial nature of HF in CLL involves disease-related factors, treatment toxicities, and traditional cardiovascular risk factors. Prompt recognition and multidisciplinary management are essential for improving outcomes. Future research should focus on developing risk stratification tools and interventions targeting acute HF in CLL patients.

Conclusion:
Acute HF poses a significant burden on CLL hospitalizations, emphasizing the need for heightened awareness and tailored management strategies. Our findings underscore the importance of early recognition and intervention to improve outcomes in this vulnerable population.
Abstract 4118387: Artificial Intelligence-Enhanced Echocardiogram Assessment Helps Distinguish Cardiomyopathy from Beat-to-Beat Variation in Atrial Fibrillation
Authors: Hong Gloria , Ouyang David , Vrudhula Amey , YUAN NEAL
Published: November 2024

Background:
Atrial fibrillation (AF) can be associated with reductions in left ventricular ejection fraction (LVEF) that improve upon conversion of AF to sinus rhythm. Such LVEF changes during AF may be due to LVEF measurement error from beat-to-beat variations related to AF itself. More precise artificial intelligence (AI)-enhanced LVEF assessment could help distinguish between such LVEF “pseudo-reduction” during AF and true cardiomyopathy, thus potentially preventing unnecessary downstream workup and treatment.

Methods:
Using a transthoracic echocardiogram database at a large academic medical center, we identified all patients whose LVEF fell below 50% while in AF who had subsequent LVEF recovery to over 50% within 90 days after converting from AF to sinus rhythm. For echocardiograms in AF, we compared the clinically assessed LVEF with AI-enhanced LVEF assessment by EchoNet-Dynamic, a validated deep learning algorithm.

Results:
In our cohort of 84 patients, the mean age was 74 years old, 36.9% were female, and 26.2% non-White. The mean LVEF recovery was 19.3% (95% CI 17.1-21.5%) after converting from AF to sinus rhythm with a mean duration of 27.4 days between the AF and sinus rhythm echocardiograms (Figure 1). For AF echocardiograms, the LVEF when reassessed by deep learning was 8.4% (6.3-10.5%) higher than the original clinical read, resulting in 30.3% of patients being reclassified as no longer having a reduced LVEF less than 50% while in AF. Among these patients with LVEF reductions during AF, 27.4% and 19.0% were given a new or worsened heart failure with reduced ejection fraction (HFrEF) diagnosis, 15.5% underwent ischemic testing, and 17.9% were started on new HFrEF medications.

Discussion:
LVEF reductions during AF can lead to new HFrEF diagnosis, workup, and treatment. However, such LVEF reductions may be temporary and partially explained by undermeasurement of LVEF during AF. AI-enhanced LVEF assessment may help reduce such measurement errors during AF and thereby prevent overdiagnosis of HFrEF. Further research is needed to understand the clinical significance of true but temporary LVEF reductions during AF.
Abstract 4119062: A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling
Authors: Deng Hanqiang , Zhang Jiasheng , Schwartz Martin
Published: November 2024

Background:
Vascular remodeling to match arterial diameter to tissue metabolic requirements commonly fails in ischemic disease. Endothelial cell (EC) sensing of elevated fluid shear stress (FSS) from blood flow induces vessel outward remodeling to restore physiological FSS, but mechanisms are poorly understood. The Smad1/5 pathway, which is maximally activated at physiological FSS and suppressed at higher flow, opposes activation of Akt, suggesting that inhibiting Smad1/5 may be required for outward remodeling.

Methods:
In vitro flow studies used ECs in a parallel plate flow chamber. In vivo mouse studies used a carotid-jugular fistula model to induce high flow outward remodeling in the carotid artery, and femoral artery ligation to examine recovery from ischemia and arteriogenesis in the hindlimb.

Results:
Suppression of Smad1/5 at high FSS is mediated KLF2-dependent induction of the BMP pathway inhibitor BMPER, which suppresses Smad1/5 and de-inhibits Akt. In a mouse arteriovenous fistula (AVF) model, high FSS induces arterial outward remodeling coincident with elevated BMPER expression and Smad1/5 inactivation. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling in the AVF and a hindlimb ischemia (HLI) model, with the latter reversed by BMP9/10 blocking antibodies (bAbs). In both STZ-induced type 1 and HFD-induced type 2 diabetic mice that show poor recovery from HLI, BMP9/10 bAbs improved outcomes.

Conclusions:
Suppression of Smad1/5 through a KLF2-BMPER pathway is required for high FSS-mediated outward remodeling. Mimicking this pathway with BMP9/10 antibodies improves vascular remodeling in diabetic mice, suggesting a potential new therapeutic approach for ischemic disease.
Abstract 4119169: Navigating Complexity: The Carlino Technique in Multivessel Percutaneous Coronary Intervention for Chronic Total Occlusion
Authors: Sohu Javeria Munir , Malik Sarah
Published: November 2024

Introduction:
Since the advent of percutaneous coronary intervention (PCI), the scope of this therapeutic intervention has broadened to include cases of life-threatening multivessel coronary artery disease that previously may have only been corrected surgically. PCI has become a common treatment of chronic total occlusion, and techniques continue to be developed to tackle more challenging cases. We present a complex case of NSTEMI with multi-vessel coronary artery disease treated with PCI via the Carlino technique.

Case Description:
A 60-year-old female with a history of hypertension, diabetes mellitus, and ischemic heart disease presented with severe chest pain that radiated to the neck and was associated with nausea and vomiting. Her EKG showed marked left-axis deviation, ST depressions in V2-V4, and RBBB. She was diagnosed with NSTEMI with a thrombolysis in myocardial infarction (TIMI) score of 5. She was loaded with aspirin and clopidogrel and was taken for left heart catheterization (LHC), which demonstrated three-vessel coronary artery disease with chronic 100% occlusion of the proximal left anterior descending artery, ostial 60-70% stenosis, and proximal 90-95% diseased left circumflex artery, while her right coronary artery had proximal 20-30% obstruction and mid 50-60% with right to left filling. The patient was advised CABG by the heart team, but the patient refused, and PCI was attempted on a shared decision basis. PCI was successful with the use of the Carlino technique: 0.5 ml of contrast dye was injected through a microcatheter to hydraulically recanalise the occlusion. The patient showed dramatic improvement and was discharged home on oral medications.

Discussion:
Treating multi-vessel coronary artery disease and CTO is challenging. PCI, particularly with the Carlino technique, offers a reliable approach. This technique, a modification of contrast-guided STAR, involves gentle contrast injection via microcatheter to modify plaque compliance and provide topographic information with regards to equipment location within vasculature, enhancing procedural success, especially in cases with impenetrable caps or calcified areas.

Conclusion:
This case is an example of how adaptive PCI techniques, such as the Carlino technique, can be employed to tackle complex instances of MvCAD that previously may have only been surgically corrected.
Abstract 4119189: Imaging practices prior to cardioversion in patients presenting post percutaneous left atrial appendage occlusion.
Authors: Bahbah Ali , Witt Dawn , Kapphahn-Bergs Melanie , Zishiri Edwin , Casey Susan , Halvorson Emily , Abdelhadi Raed , Sengupta Jay
Published: November 2024

Background:
Direct current cardioversion (DCCV) carries a risk for stroke in AF patients, for that reason there are guidelines for mitigating this risk in AF patients on oral anticoagulation (OAC). Meanwhile, no consensus on the best approach for cardioverting patients with an appendage occlusion device in situ. This led to a very wide variation in pre and post DCCV practices in these patients.

Aims:
We aim to explore different factors that might be associated with the variation seen in pre-DCCV imaging practices in patients presenting post- percutaneous LAAO.

Methods:
This was a multi-center retrospective cohort study of patients who received DCCV for AF or AFL during follow up after LAAO procedure within a single healthcare system from 2016-2024.

Results:
A total of 119 patients were included, there were more females 70 (59%), with more than half (64 (54%)) receiving a first-generation WATCHMAN™ 2.5, while the rest had WATCHMAN FLX™. Median age at presentation was 77 years (72,82), BMI of 31 kg/m
2
(26,37), average CHADSVASC score of 4.5 and HASBLED score of 3. A median duration of 10 months (3,21) between LAAO to presentation for DCCV . Forty-four (37%) patients had pre-DCCV imaging (imaging cohort). Number of males was significantly higher in the imaging cohort (24 (54.5%) vs 25 (33.3%), p=0.038), compared to those without imaging. There was a significant difference (p<0.001) between the two cohorts in the location (center) where DCCV was done. The site with the highest number of pre-DCCV imaging cases had an equal gender ratio of patients presenting for DCCV. Patients who received imaging presented earlier (11.2 months vs 15.8 months, p=0.068) compared to those without imaging, though the difference was not significant. Between the two groups, there was no significant difference in OAC (VKA-antagonist/DOAC) usage prior to presentation (8 (18.6%) vs 12 (16.4%), P=0.9). There was no significant difference in baseline CHADSVASC score, HASBLED score, age, LVEF. Higher percentage of patients were discharged on OAC post DCCV in the imaging arm (13 (30.2%) vs 14 (19.4%), p=0.27), but the difference was non-significant. No Device related thrombus nor significant PDL was detected on imaging.

Conclusion:
There was male preference in providing pre-DCCV imaging for ruling out DRT. Location of care was also associated with the variation in pre-DCCV protocols. Additional research is needed to understand other factors associated with variation seen in pre-DCCV practices.
Abstract 4119210: Differential Proteomic Expression of IGFßP-1 and IGFßP-2 in Primary Angioplasty for Acute Myocardial Infarction
Authors: Kim Jin Un , Little Callum , Acquah Vanessa , Ponticos Markella , Kotecha Tushar , Rakhit Roby
Published: November 2024

Introduction:
Insulin growth factor (IGF) binding protein-1 and 2 (IGFBP-1 and 2) are implicated in acute myocardial infarction (AMI) and have been suggested as predictors of mortality and development of heart failure. The IGF axis has been shown to play roles in cell proliferation and apoptosis. We analysed the serum IGFBP-1 and 2 levels in AMI before and after percutaneous coronary intervention (PCI) and correlated this with cardiac magnetic resonance (CMR) imaging to better establish their significance as biomarkers in AMI.

Methods:
Patients with AMI who presented to Royal Free Hospital, London, were recruited for proteomic analysis (O link Proximity Extension Immunoassay) at presentation, 24h and 72h following primary PCI. All underwent both admission and follow-up CMR at 6 months to assess for myocardial oedema, left ventricular volumes and function, and assessment of scar.

Results:
Proteomic evaluation in 20 AMI patients (male 95%; median age 59) revealed significant reduction in the average IGFBP-1 values at discharge compared with presentation, from 5.93 to 4.52 (24% reduction, p=0.003). Conversely, the average IGFBP-2 values at discharge significantly increased from 7.66 to 8.29 (8% increase, p=0.001). Higher discharge IGFBP-2 value was also correlated with increased indexed left ventricle end diastolic volume (LVEDV) at 6-month follow-up (R=0.54, p=0.032).

Discussion:
IGFBP-1 and 2 showed significant change following intervention for AMI. IGFBP-1 is a stress hormone, which is directly and indirectly activated by cytokines, dysglycaemia and vasopressin activation. Its subsequent reduction following PCI in AMI indicates relative resolution of inflammation, but this was not correlated with changes in infarct size or LV function at follow-up. IGFBP-2 showed significant upregulation, and higher values at discharge were significantly correlated with increased LDEDV at follow-up, suggesting adverse clinical outcomes within this setting. This data suggests differential roles of IGFBP-1 and 2 in the pathogenesis of AMI.
Abstract 4119250: Partial versus Full ECMO Support in Combined Cardiogenic and Septic Shock – ELSO Registry Analysis
Authors: Granger Hannah , Rali Aniket , Labrada Lyana , Alarfaj Mohammad , Tran Lena , hu jinxiang , Baker Jordan , Rali Taylor , Bacchetta Matthew , Anders Marc , Tonna Joseph , Lindenfeld Joann , Shah Zubair
Published: November 2024

Background:
There remains paucity of data on patient outcomes with combined cardiogenic and septic shock requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. While guidelines exist on target VA-ECMO flow in cardiogenic shock patients, optimal (partial versus full) flow in combined shock remains largely unknown.

Methods:
We queried the Extracorporeal Life Support Organization registry to identify patients in combined cardiogenic and septic shock supported with VA-ECMO between 2017 and 2022. Patients were categorized into either partial or full ECMO support based on ECMO flow at 24 hours indexed to body surface area. Partial support was defined as < 2.2 liters/m2 while full support was ≥2.2 liters/m2. Patients with other forms of mechanical circulatory support, VA-ECMO as bridge to advanced therapies or discharged on VA-ECMO were excluded from the analysis. Primary outcome of interest was survival to discharge. Baseline characteristics including center volumes and Charlson co-morbidity index were compared between survivors and non survivors. Predictors of mortality were identified using multivariable logistical regression model.

Results:
A total of 452 patients with combined shock supported with VA-ECMO were identified. Overall mortality was 63%. Patients that survived to discharge were younger (46.3 vs 53 years, p < 0.001) and had lower BMI (29.3 vs 31.1, p = 0.041), Charlson co-morbidity index (1.4 vs 2.0, p = 0.01) and rates of pre-ECMO cardiac arrest (28.7% vs 39.4%, p = 0.023). Survivors were also more likely to be at high [> 25 ECMO runs per year] volume centers compared to low [≤ 10 ECMO runs per year] volume centers (62.3% vs 20.4%, p = 0.04). Patients receiving full ECMO support had a higher likelihood of survival to discharge than partial support (42.6% vs 33.8%, p = 0.063), although it did not reach statistical significance. [Table 1] Indexed VA-ECMO flow at 24 hours was also associated with improved outcomes when assessed as continuous variable. [ Figure 1] Advanced age [aOR 1.02, 95% CI 1.01-1.04, p < 0.001], pre-ECMO cardiac arrest [aOR 1.71, 95% CI 1.11-2.65, p = 0.016] and baseline Charlson co-morbidity index [aOR 1.13, 95% CI 1.01-1.28, p = 0.043] were all associated with increased mortality after adjustment for baseline differences.

Conclusion:
Mortality among patients requiring VA-ECMO for combined cardiogenic and septic shock is high. Full circulatory support may be associated with improved survival in this cohort.
Abstract 4119744: Evaluation of Neuropsychological development and Factors Affecting it in Children With Cyanotic and Acyanotic Congenital Cardiac Disease After Surgical Treatment
Authors: Lin Shuantong , Su Xiaojun , Guan Yulong , Cao Dequan
Published: November 2024

Objective:
To evaluate neuropsychological development in children with cyanotic and acyanotic congenital heart diseases (CHDs) after surgical treatment and analyze the risk factors.

Methods:
89 children who received follow-up in Fuwai Hospital after surgical treatment of CHDs were recruited in this study and 90 normal children were recruited as the control group. The children with CHDs were divided into cyanotic CHDs group and acyanotic CHDs group. Neuropsychological development was assessed according to Pediatric-psychological mental test scale and statistical analysis was employed.

Results:
The acyanotic CHDs group achieved better distribution of development quotient than cyanotic CHDs group (p < 0.05) but worse than the normal control group (p = 0.004). The proportion in cyanotic CHDs group with developmental quotient below the moderate level was higher than that of the normal control group (p < 0.001), but there was no significant difference between the cyanotic CHDs group and acyanotic CHDs group (p = 0.055). Multivariate regression analysis indicated that for cyanotic CHDs group, younger age at cardiac surgery, lower body mass, lower preoperative blood glucose level, lower BIS level, and prolonged duration of tracheal intubation after surgery were linked with lower scores in the test scale (p < 0.05); for acyanotic CHDs group, younger age at cardiac surgery, lower body mass, lower temperature during surgery and prolonged duration of tracheal intubation after surgery were linked with lower scores in the test scale(p < 0.05).

Conclusion:
Distinct neuropsychological impairment could be present in children with cyanotic CHDs. Younger age at cardiac surgery, body mass, preoperative blood glucose level, BIS level during surgery, temperature during surgery and duration of tracheal intubation after surgery were perioperative factors that could influence long-time neuropsychological development in children with CHDs.
Abstract 4119868: Statin and PCSK9 Inhibitor Utilization and Spending in Medicaid between 2018 to 2022: A National Analysis
Authors: Beschloss Alexander , Wadhera Rishi , Oseran Andrew
Published: November 2024

Introduction:
Low-income working-aged adults in the Medicaid program have a high burden of cardiovascular risk factors and disease, but often face barriers accessing necessary therapies. Little is known about contemporary patterns of utilization and spending on lipid-lowering therapies in Medicaid programs.

Goal:
To evaluate national trends in utilization and spending on statins and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in Medicaid.

Methods:
We performed a serial cross-sectional study using the Medicaid Spending by Drug Database, which contains national-level Medicaid spending data for medications partially or fully reimbursed by Medicaid for the approximately 84 million beneficiaries. We evaluated annual trends in utilization (prescription fills) and total spending for statins and PCSK9i from 2018 to 2022, both overall and by individual drug formulation. Spending was adjusted for inflation and reported in 2022 US dollars.

Results:
Medicaid beneficiaries filled 20.4 million statin prescriptions in 2018 compared to 20.3 million in 2022, representing a 0.4% decrease. However, Medicaid spending on statins decreased by 7.1%, from $246.2 million to $226.8 million over the same period. Prescription fills for generic Rosuvastatin increased the most (0.79 million to 2.6 million, +224.2%), while fills for brand-name Crestor decreased the most (0.065 million to 0.003 million, -95.2%). Medicaid beneficiaries filled 121,737 prescriptions for PCSK9 inhibitors in 2022 compared to 7,617 in 2018 (+1498%), coinciding with a 640% increase in total spending ($8.9 million to $65.7 million). Repatha Sureclick was the most filled PCSK9i in Medicaid with 80,503 fills in 2022, representing $43.9 million in total Medicaid spending.

Conclusions:
Despite almost no change in statin utilization between 2018 and 2022, Medicaid spending on statins fell by approximately $20 million, driven by a shift from brand-name to generic formulations. In contrast, spending on PCSK9 inhibitors increased by $57 million as these medications became more widely used. Understanding these trends is critical as Medicaid programs work to ensure access to effective cardiovascular therapies while also identifying opportunities for cost efficiencies nationwide.
Abstract 4119941: Identification of individuals who benefit from omega-3 fatty acid supplementation to prevent coronary heart disease: A machine-learning analysis of the VITAL
Authors: Hamaya Rikuta , Cook Nancy , Sesso Howard , Mora Samia , Buring Julie , Manson JoAnn
Published: November 2024

Backgrounds:
Randomized controlled trials (RCTs) have demonstrated benefits of marine omega-3 polyunsaturated fatty acids (omega-3 FA) supplementation for the prevention of coronary heart disease (CHD). However, it has not been clear which individuals would benefit the most from the supplementation. We sought to predict the individual treatment effect of omega-3 FA supplementation on CHD prevention and to develop an omega-3 effect score to stratify individuals according to their expected benefit from the supplementation.

Methods:
Among the 25,871 randomized participants without history of CVD in the VITamin D and OmegA-3 TriaL (VITAL), we applied machine-learning (ML) approaches to predict individual treatment effect of omega-3 FA supplementation on 5-year CHD risk (a composite of myocardial infarction, coronary revascularization, and CHD death) using 11 covariates pre-specified in the VITAL trial protocol. A 10-fold cross-validation was used and held-out test dataset was used for the evaluation. An omega-3 effect score was developed such that each covariate contributed linearly, and utility of the score was further evaluated by transportability analysis using the National Health and Nutrition Examination Survey (NHANES) data as the target population.

Results:
Omega-3 FA intervention led to absolute 0.48% [SE: 0.20] reduction in CHD in the total population. ML algorithms effectively stratified participants by their expected benefit according to individual factors; decreased CHD risk was observed in those with quintile 1 and 2 of the expected benefit (absolute CHD risk reduction %: 1.30 % [0.55] and 1.32 % [0.51] in quintile 1 and 2, respectively). Race, diabetes, and fish intake most contributed to the omega-3 effect score. CHD incidence rates per 1000 person-year were 5.5 [0.44] if treated and 8.5 [0.55] if not treated (35.3% reduction) in individuals with the score ≥11 (upper 40th percentile), and 3.9% [0.31] if treated and 3.4% [0.55] if not treated (14.7% increase) in those with the score <11, respectively. The transportability of the utility of the score to baseline NHANES data was confirmed.

Conclusion:
In VITAL, ML approaches identified individuals who experienced greater CHD reduction from the omega-3 FA intervention, and an omega-3 effect score stratified the expected benefit. Although it warrants testing in a new RCT, the omega-3 effect score holds promise for guiding the indication of omega-3 FA supplementation in US primary prevention population.
Abstract 4120249: What Happens to Automated External Defibrillator Rhythm Strips after a Cardiac Arrest?
Authors: Ashur Carmel , Zirille Francis , Varosy Paul , Sandhu Amneet , Tumolo Alexis , Rosenberg Michael , Garg Lohit , Sabzwari Syed Rafay Ali , Barrett Christopher , Cerbin Lukasz , Saqi Bilal , Varela Daniel , Adewumi Joseph , Zipse Matthew , Tzou Wendy , Aleong Ryan
Published: November 2024

Background:
Following an out of hospital cardiac arrest (OHCA), rhythm strips stored on an automated external defibrillator (AED) help guide important medical decisions, including possible implantable cardioverter defibrillator (ICD) implantation. However, this information is often difficult to obtain.

Objective:
To evaluate how frequently AED rhythm strips are reviewed following an OHCA prior to placing an ICD.

Methods:
Using the Cardiac Arrest Registry to Enhance Survival (CARES), we identified patients from 1/2015-12/2023 who were transferred to our institution following an OHCA. Patients were excluded if resuscitation was not attempted, death occurred during the hospitalization or patient identifying information was not available.

Results:
Of 907 OHCAs identified, 119 patients (
Table 1
) met the inclusion criteria. The AED rhythm strip was in the electronic medical record on hospital arrival in 22% of cases and only after provider initiation in 6% of cases. None of the rhythm strips from a bystander-only delivered AED shock (n=17) were available on arrival, with only 24% retrieved during the hospitalization, taking 4.5±2.1 days from the date of arrest. Patients with an AED rhythm strip available (n=34) were more likely than those without a rhythm strip (n=85) to have a cardiac MRI (38% v. 13%, p=0.02) and genetic testing (15% v. 1%, p=0.02) done and have an ICD placed (53% v. 27%, p=0.04) or be discharged on a new anti-arrhythmic drug (15% v. 4%, p=0.04).
Figure 1
Of the 42 patients who had an ICD placed during the index hospitalization, 54% were implanted without knowing the type of shockable rhythm or confirmation that an appropriate AED shock had been delivered.

Conclusion:
Rhythm strips help guide clinical decisions when assessing the need for ICD implantation. There is a systems gap in the process of transferring rhythm strips from AEDs to hospital providers following an OHCA.
Abstract 4120290: Sex-specific Impact of Early to Mid-gestational Testosterone Excess on Sheep Fetal and Adult Offspring Lungs
Authors: Razan Md Rahatullah , Woo Kel Vin , Bernal David , Padmanabhan Vasantha , Vyas Arpita
Published: November 2024

Using the translationally relevant sheep model of prenatal testosterone (T) excess, we previously reported intrauterine growth retardation (IUGR) in both sexes, adverse sex specific programming of fetal heart and cardiometabolic dysfunction in adult female offspring. Because of the intricate reciprocal relationship between the heart and lungs, we
hypothesized
that gestational T excess will have detrimental sex-specific effects on offspring lungs beginning as early as fetal life and extending into adulthood. Pregnant ewes were intramuscularly injected with 100 mg of testosterone propionate twice weekly from gestational days (GD) 30-90 (term 147 days) and offspring lungs were harvested at GD120, 30 days after cessation of T treatment; (n=4-7/group) and in adulthood (n=4-6/group) and processed for molecular and histological analyses. Data was analyzed by student T test within each sex and Cohen (d) effect size was calculated (Cohens d>0.8 represents large effect size. Lung collagen was significantly increased in T-male fetuses (TM) vs control males (CM) (p=0.01, d=1.99) that persisted into adulthood (TM vs CM: p=0.01, d=1.83). The effects of gestational T excess was evidenced as an increase in collagen only in the lungs of adult T-female fetuses (TF) relative to control females (CF) (p=0.003, d=2.38), but not during fetal life. Gestational T excess induced significant parallel increases in TUNEL positive nuclei/frame in TM fetuses relative to CM (n=3/group, p=0.01, d=3.35) persisting as a large magnitude increase of TUNEL positive nuclei/frame in adult TM (p=0.12, d=0.96). In TF females, apoptotic changes were not noted in fetal lungs but an increase of TUNEL positive nuclei/frame was evidenced in adult TF (p=0.08, d=1.14). At the molecular level prenatal T excess induced an increase in histone deacetylase 1 (HDAC1) expression in fetal TM vs CM (p=0.04, d=1.50), and decrease in HDAC1 in TF vs CF (p=0.10, d=1.09) suggestive of T-induced epigenetic alteration. Transcriptomic analysis of fetal lungs revealed upregulation of pathways associated with estrogen signaling and neuroactive ligand receptor interaction, and downregulation of pathways associated with protein processing in endoplasmic reticulum and antigen processing&presentation (unadjusted p< 0.05, log FC>1.5) in both sexes. Overall, early to mid-gestational exposure to testosterone adversely reprograms the lungs in sex specific fashion as early as fetal life extending into postnatal adult life.
Abstract 4120312: Patient Perspectives on Barriers and Facilitators to Familial Hypercholesterolemia Cascade Testing Through the Lens of the Socio-Ecological Model
Authors: Morgan Kelly , Gilbert Klaczko Christie , Walters Nicole , Brangan Andrew , Tricou Eric , Betts Megan , Gabriel Jazmine , Lindsey-Mills Zoe , McGowan Mary , Rahm Alanna , Sturm Amy , Jones Laney , Campbell-Salome Gemme
Published: November 2024

Background:
Low uptake of Familial Hypercholesterolemia (FH) cascade testing, the stepwise identification of at-risk relatives, leads to missed opportunities for atherosclerotic cardiovascular disease (ASCVD) prevention. The IMPACT-FH study offered strategies (packet, chatbot, and direct contact) to support FH cascade testing.

Hypothesis:
We hypothesized that IMPACT-FH strategies would facilitate cascade testing uptake and overcome persistent barriers to cascade testing.

Aim:
We aimed to understand barriers and facilitators to FH cascade testing in the context of the socio-ecological model (SEM) which provides a framework to examine the interconnected influences of intrapersonal, interpersonal, institutional, community, and policy levels.

Methods:
Semi-structured interviews were conducted with IMPACT-FH study participants. The SEM informed qualitative analysis to identify barriers and facilitators to FH cascade testing.

Results:
A total of 15 FH probands (initial family member tested) and 12 relatives were interviewed, of whom the majority (59%) were female with an average age of 55.7 years. All relatives completed cascade testing. At the interpersonal level, probands reported that relatives’ attitudes about high cholesterol, including seriousness and treatability, were a barrier or facilitator to cascade testing. Probands explained how relatives’ beliefs were informed by interactions with their clinicians and societal beliefs about cholesterol (i.e., medication stigma). Interpersonally, probands described challenges overcoming relatives’ beliefs and a reluctance to encourage relatives to complete testing despite the availability of novel strategies. Probands and relatives reported that insurance policies and concerns about testing costs informed cascade testing decision-making. Institutional strategies to provide low-cost testing and cost transparency were described as facilitators. Variable access to clinicians with genetics expertise and licensure laws were described as barriers by out-of-state relatives. Probands and relatives agreed that strategies providing direct access genetics expertise (i.e., direct contact, chatbot) helped address these barriers.

Conclusion:
The IMPACT-FH study ameliorated barriers at higher levels of the SEM related to access to genetics expertise and cost. Intra- and interpersonal barriers remained challenging to overcome. To improve FH detection and ASCVD prevention, it is important to address barriers at all levels of the SEM.
Abstract 4120375: Penetrance and Phenotype Conversion Rate of Genetic Hypertrophic Cardiomyopathy in an Academic Biobank
Authors: Shin Joseph , Small Aeron , Zawatsky Carrie , Fifer Michael , Tower-rader Albree , Green Robert , Lebo Matthew , Natarajan Pradeep
Published: November 2024

Introduction:
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant condition with incomplete penetrance and variable expressivity. Given the increasing prevalence of sequencing and current guidelines on secondary finding disclosure, HCM P/LP alleles are increasingly being returned to patients who undergo genetic testing for other reasons. Whether individuals carrying P/LP HCM variants discovered in a genome-first context have progressive endophenotypes indicative of HCM remains poorly understood.

Methods:
To evaluate the penetrance and phenotype conversion rate of adults with P/LP HCM variants, we leveraged the Massachusetts General Brigham Biobank (MGBB), which consists of 36,417 participants with genotyping array and clinical data. Primary images of the earliest and latest TTE studies were reviewed for measurements of the posterior wall (PW), interventricular septum (IVS), and left ventricular morphology. Phenotype-positive (P+) status was defined by a PW or IVS thickness of at least 13 mm.

Results:
P/LP HCM variants were identified in 42 (0.1%) individuals with mean (SD) age 50.0 (16.6) years and 21 (50%) female sex. The most common HCM variants were in MYBPC3 (44%) and MYH7 (40%), followed by TNNI3(7%), MYL3 (7%), and TNNT2 (2%). Among the 42 genotype-positive (G+) individuals in MGBB, 17 (40%) had pre-existing HCM diagnoses prior to genomic return of results (gRoR). In contrast, 25 (60%) G+ individuals lacked a prior HCM diagnosis, among whom gRoR prompted TTE studies in 13 patients, revealing evidence of HCM in 9 individuals. Among the 42 G+ patients, 25 (58%) patients had completed at least two TTE studies, with a median [IQR] of 6 [3-9] TTE studies per patient, across a span of 10 [7-15] years follow-up. At the time of first TTE, 16 (64%) patients were P+ while 9 (36%) were P-. No G+, P- individuals converted to P+ over 10 years follow-up, nor was there any significant change in IVS or PW thickness. In contrast, individuals who were P+ at the initial TTE exhibited thickening PW (25% increase, CI 97.5% of 6 to 44) and IVS (26% increase, CI 97.5% of 4 to 49) over 8 years follow-up.

Conclusion:
In a genome-first approach, we identified 42 individuals in the MGBB with a P/LP HCM variant, among whom 60% lacked a prior clinical diagnosis of HCM. Targeted phenotyping revealed that nearly half of this newly identified group were P+. Over a median of 10 years follow-up, we observed a 0% phenotype conversion rate among G+, P- adult carriers of HCM variants.
Abstract 4120469: Racial and ethnic disparities in catheter based interventions vs. open heart surgery in congenital heart disease
Authors: Nguyen Michael , Chang Ruey-Kang , Rehan Virender , Sakai Bizmark Rie
Published: November 2024

Introduction:
Transcatheter cardiac interventions have emerged as a viable alternative to open heart surgery for specific congenital heart disease lesions. There is literature to support racial and ethnic disparities in medicine, indicating that patients from racially and ethnically marginalized populations are less likely to receive advanced less invasive procedures. This study seeks to delve into the existence of such inequities between transcatheter and surgical interventions, shedding light on potential inequalities in access and outcomes.

Methods:
We analyzed California and Florida's State Inpatient and Ambulatory Surgery Databases from 2005 to 2017 to study patients under 18 admitted with diagnosis of atrial septal defect, pulmonary stenosis, aortic stenosis, and ventricular septal defects. Multivariable logistic regression, adjusted for patient characteristics, assessed race and ethnicity's influence on procedure type and in-hospital mortality. We also used log-transformed linear regression to examine associations with length of stay, hospitalization cost, and cost per day.

Results:
We identified 13,771 records who had open surgeries, and 2,045 records who had CBI. Compared to non-Hispanic White patients, Black patients were significantly more likely to undergo open surgical procedures (adjusted Odds Ratio [aOR] 1.49, p < .001). Additionally, Black, Hispanic, and other race patients had higher risks of in-hospital death (aOR 1.92, p = 0.016 for Black; aOR 1.93, p < 0.01 for Hispanic; aOR 2.37, p < 0.01 for other races). Black and Hispanic patients also experienced longer lengths of stay (Adjusted Means Ratio [aMR] 1.34, p < 0.01 for Black; aMR 1.16, p < 0.01 for Hispanic), and higher costs (aMR 1.12, p = .01 for Black; aMR 1.11, p = .01 for Hispanic), but Black patients had a lower cost per day (aMR 0.96, p = .02).

Conclusion:
Racial and ethnic gaps persist in pediatric cardiac care, with Black patients facing reduced access to less invasive procedures, higher mortality rates, longer hospital stays, and increased costs compared to non-Hispanic whites. However, the higher costs are likely attributed to longer hospital stays rather than expensive interventions. It is imperative to tackle these disparities to prioritize patient-centered care and streamline resource allocation in healthcare.
Abstract 4120821: Electrochemical Impedance Spectroscopy Unmasks High-Risk Atherosclerotic Features in Human Coronary Artery Disease
Authors: Chen Michael , Suwanaphoom Krit , Sanaiha Yas , Luo Yuan , Benharash Peyman , Fishbein Michael , Packard Rene
Published: November 2024

Background:
Coronary plaque rupture remains the prominent mechanism of myocardial infarction. Accurate identification of rupture-prone plaque may improve clinical management. This study assessed the discriminatory performance of electrochemical impedance spectroscopy (EIS) in human cardiac explants to detect high-risk atherosclerotic features that portend rupture risk.

Methods:
In this single-center, prospective study, n=26 cardiac explants were collected for EIS interrogation of the three major coronary arteries. Vessels in which advancement of the EIS catheter without iatrogenic plaque disruption was rendered impossible were not assessed. N=61 vessels underwent EIS measurement and histological analyses. Plaques were dichotomized according to previously established high rupture-risk parameter thresholds. Diagnostic performance was determined via receiver operating characteristic areas-under-the-curve (AUC).

Results:
Necrotic cores were identified in n=19 vessels (median area 1.53 mm
2
) with median fibrous cap thickness of 62 μm. Impedance was significantly greater in plaques with necrotic core area ≥1.75 mm
2
vs <1.75 mm
2
(19.8±4.4 kΩ vs 7.2±1.0 kΩ,
P
=0.019), fibrous cap thickness ≤65 μm vs >65 μm (19.1±3.5 kΩ vs 6.5±0.9 kΩ,
P
=0.004), and ≥20 macrophages per 0.3 mm-diameter high-power field (HPF) vs <20 macrophages per HPF (19.8±4.1 kΩ vs 10.2±0.9 kΩ, P=0.002). Impedance identified necrotic core area ≥1.75 mm
2
, fibrous cap thickness ≤65 μm, and ≥20 macrophages per HPF with AUCs of 0.889 (95% CI: 0.716–1.000) (
P
=0.013), 0.852 (0.646—1.000) (
P
=0.025), and 0.835 (0.577—1.000) (
P
=0.028), respectively. Further, phase delay discriminated severe stenosis (≥70%) with an AUC of 0.767 (0.573—0.962) (
P
=0.035).

Conclusions:
EIS discriminates high-risk atherosclerotic features that portend plaque rupture in human coronary artery disease and may serve as a complementary modality for angiography-guided atherosclerosis evaluation.
Abstract 4120856: Abdominal Aortic Blood Flow and Interstage Growth and Neurodevelopment in Patients with Single Ventricle Heart Disease
Authors: Abumregha Osama , Lee Fu-Tsuen , Chetan Devin , Tedesco-Bruce Anna , Herridge Joann , Gibson Erika , Honjo Osami , Sananes Renee , Ly Linh , Seed Mike , Floh Alejandro
Published: November 2024

Background:
Achieving normal somatic growth and neurodevelopmental (ND) milestones is a common challenge for children with single ventricle heart disease (SV) prior to stage 2 palliation (S2P). This study aimed to characterize the potential association with poor splanchnic and cerebral circulations.

Methods:
This retrospective single centre study included SV patients born February 1, 2012, to May 30, 2022 who underwent MRI evaluation and S2P <12 months of age. Blood flow indices, including descending aorta flow (DAoNet), were measured by phase-contrast MRI. Primary outcomes were weight-for-age Z score (WFAZ) at S2P, and 18-month ND outcomes measured by Bayley Scales of Infant and Toddler Development 3rd Ed. Spearman’s correlation was used to model associations; statistical significance was considered for p<0.05.

Results:
A total of 144 patients were included: 61% (n=88) male, 12% (n=17) with genetic anomalies/syndrome, median (interquartile range) gestational age was 38.7 (38, 39.6) weeks, birth weight of 3.2 (2.8-3.6) kg, and birth WFAZ -0.23 (-1.1-0.6). Stage-1 palliation (n=130) was completed at 6 (3-23) days, 34% (n=49) for hypoplastic left heart syndrome, and S2P at 6.1 (5.3-7.1) months with a WFAZ of -1.4 (-2.3- (-0.5)). S2P WFAZ did not correlate with DAoNet (Figure 1), systemic cardiac output, or other blood flow indices. Lower S2P WFAZ was associated with lower birth WFAZ, and perioperative gastrointestinal complications. Lower 18-month motor development score was associated with lower birth WFAZ, native high pulmonary blood flow physiology, and indices of increase pulmonary blood flow: superior vena cava flow (b=8.8; [95% CI: 0.7 to17], p=0.03) and pulmonary venous to systemic blood flow (Qp:Qs) (b=-7, [95% CI: -11.1 to -2.9], p=0.001). Other ND domains were associated with lower birth WFAZ, not blood flow indices.

Conclusion:
In SV patients, DAoNet did not correlate with growth at S2P. Modifiable factors studied were not associated with somatic growth. DAoNet, superior vena cava flow, and Qp:Qs were associated with 18-months motor development, which may indicate long-term risks of high pulmonary blood flow. Studies are needed to delineate the pathophysiology by which these findings are mediated.
Abstract 4120918: Prevalence Of Prediabetes According To Sleep Apnea Status
Authors: Um Yoo Jin , Cho Sung-il
Published: November 2024

Aim:
The association between obstructive sleep apnea and prediabetes using STOP-Bang questionnaire is unknown. We aimed to investigate prevalence of prediabetes among people according to sleep apnea status.

Methods:
This cross-sectional study included 10131 Korean adults without diabetes with information of STOP-Bang score were identified from the dataset of the Korea National Health and Nutrition Examination Survey 2019-2021. Prediabetes was categorized into three subsets: fasting blood glucose only (fasting blood glucose 100-125 mg/dL, HbA1c <5.7%), HbA1c only group (fasting blood glucose <100mg/dL, HbA1c 5.7-6.4%) and both fasting blood glucose and HbA1c group (fasting blood glucose 100-125mg/dL, HbA1c 5.7-6.4%). We used multivariable logistic regression to see the odds ratio and 95% confidence intervals for prediabetes.

Results:
There were 3828 subjects who reported STOP-Bang score of ≥3, which shows increased risk of OSA. Multivariable-adjusted odds ratio (95% confidence interval) for prediabetes meeting both fasting blood glucose and HbA1c comparing STOP-Bang score of ≥3 with <3 was 1.06 (1.01-1.12). In further evaluation of separate gender groups, statistically significant results were seen in women. The multivariable adjusted result correlated with that of the total population. (odds ratio 1.20, 95% confidence interval 1.10-1.30) This was more prominently seen in postmenopausal women. (odds ratio 1.21, 95% confidence interval 1.11-1.32)

Conclusion:
In Korean general population, the odds of the risk of obstructive sleep apnea was significant in prediabetes group meeting both fasting blood glucose and HbA1c, especially in postmenopausal women.
Abstract 4120919: Cell physiology and multi-omics analysis revealed disordered embryogenesis as early as mesoderm specification in models of Holt-Oram Syndrome
Authors: Satoh Masahiro , Teramoto Ryota , Victorio Rachelle , Goto Shinichi , Zhu Wandi , Homilius Max , Kaveh Aryan , Chiang David , Saha Kusumika , Zu Yao , KC Ashmita , Beerens Manu , Macrae Calum
Published: November 2024

Introduction:
Congenital heart diseases (CHDs) are the leading cause of childhood morbidity and mortality. The dysregulation of several cardiac transcription factors (TFs) leads to CHD. The coordination of several cardiac TFs is required and essential for cardiogenesis. However, the mechanisms to acquire its cardiac cell identity remain unclear.

Hypothesis:
Mutant
Tbx5
dysregulates embryogenesis during mesoderm specification, prior to its expression in the tissues in Holt-Oram syndrome.

Methods:
Using cellular physiology and multiomics analysis in both human ES cells and a zebrafish model of
TBX5
germline mutation. we evaluated embryonic structure and function, prior to the onset of gastrulation in the context of both heterozygous and homozygous
TBX5
mutation.

Results:
Zebrafish time course transcriptome profiles over gastrulation revealed that loss of
Tbx5
impacted transcriptional profiles at the blastula stage. Single cell RNA sequencing (scRNA-seq) on 16243 zebrafish blastula stage cells showed loss of
Tbx5
impacted transcription noise at the blastula stage prior to the expression of zygotic
Tbx5
with associated effects on chromatin accessibility using omni-assay for transposase-accessible chromatin (ATAC) and evidence of aberrant Wnt signaling even at the blastula stage. Embryo-wide cell structure and function were abnormal in both
Tbx5
mutant zebrafish heterozygotes or homozygotes. To validate Undifferentiated human ES cell H3K4me3 Cleavage Under Targets&Release Using Nuclease (CUT&RUN) also showed abnormal Wnt signaling in
TBX5
homozygous mutation and
TBX5
CUT&RUN showed aberrant mesoderm pathway. Calcium imaging analysis demonstrated the lowest excitation frequency in
TBX5
homozygous mutation prior to mesoderm specification.
TBX5
homozygous human ES derived mesoderm cells exhibited low expression levels of mesoderm marker genes compared to
TBX5
wild type mesoderm.

Conclusion:
Integrating single cell physiology and multi-omics technologies, we idneifified fundamental dysregulation of embryogenesis in mutant cardiac-restricted gene disorder prior to mesoderm specification or the zygotic expression of the mutant gene. These findings suggest that
Tbx5
started to determine cell fate prior to mesoderm specification by altering chromatin accessibilities and histone modification.
Tbx5
affected mesoderm differentiation by influencing Wnt signaling and cell physiology.