bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4134306: Menopausal Status Protects Against Vascular Dysfunction Induced by Breast Cancer Chemotherapy
Authors: Szczepaniak Piotr , Mikolajczyk Tomasz , Jozefczuk Ewelina , Hodorowicz-Zaniewska Diana , Streb Joanna , Jurczyk Jakub , Gara Katarzyna , Siedlinski Mateusz , Krolczyk Jaroslaw , Sulicka-Grodzicka Joanna , Laksa Iwona , Grodzicki Tomasz , Guzik Tomasz
Published: November 2024

Introduction:
Breast cancer chemotherapy is associated with an increased risk of cardiovascular events, particularly pronounced in postmenopausal women. Vascular damage and docetaxel-caused endothelial dysfunction may underlie these effects, although the role of estrogens and menopausal status remains undefined.

Hypothesis:
Estrogens protect premenopausal women from neoadjuvant chemotherapy-induced endothelial dysfunction (NACT regimen: docetaxel, doxorubicin, cyclophosphamide) and its component docetaxel.

Methods:
We studied vascular function and its molecular determinants in mammary artery branches from pre- and postmenopausal women undergoing breast cancer surgery, with or without prior NACT. Mechanisms were investigated in bilaterally ovariectomized female C57BL/6J mice treated with docetaxel or placebo.

Results:
While NACT evoked endothelial dysfunction characterized by the loss of nitric oxide bioavailability in blood vessels from postmenopausal women, premenopausal women were protected from this phenomenon
(Fig. 1)
. Furthermore, premenopausal women’s blood vessels exhibited resilience against NACT-induced vascular oxidative stress. In particular, NOX4 expression was markedly lower in NACT-treated arteries from premenopausal women compared to their postmenopausal counterparts. No differences were seen in the non-NACT groups. At the molecular level, NACT incited lower inhibitory phosphorylation of Thr495 eNOS in premenopausal women's arteries compared to those of postmenopausal women post-NACT. In mice following bilateral ovariectomy, docetaxel caused endothelial dysfunction, but did not perturb acetylcholine-induced vasodilation in non-ovariectomized mice. Docetaxel induced blood pressure only in the group of ovariectomized mice.

Conclusions:
NACT-induced vascular dysfunction, often observed in breast cancer survivors, is absent in premenopausal women. This can be partially attributed to the protective role of estrogens, which prevent excessive production of reactive oxygen species and inhibitory eNOS phosphorylation.
Abstract 4134308: Re-evaluating the safety profile of Semaglutide: An updated meta-analysis
Authors: Rivera Frederick , MANGUBAT GERARD FRANCIS , Magalong John , Ansay Marie Francesca , Zelenkov Nenad , vijayaraghavan krishnaswami , Ruyeras Jade Monica Marie , Amigo John Andrew , Ong Kenneth , Mahilum Mer Lorraine
Published: November 2024

Background:
Semaglutide is increasingly used in the management of type 2 diabetes mellitus and obesity. Ensuring safety of this medication is crucial for its clinical use. This meta-analysis evaluates the safety profile of semaglutide across patient populations and treatment durations.

Methods:
Randomized controlled trials assessing the safety of semaglutide versus placebo, with specified treatment durations were identified. The primary outcome was occurrence of any cardiovascular adverse events. Secondary outcomes included sudden cardiac death, adverse events leading to death, adverse events, gastrointestinal side effects, occurrence of hypoglycemia and new-onset neoplasm.

Results:
A total of 23 studies met the inclusion criteria with a combined sample size of 57,911 participants. The meta-analysis revealed that the adverse event associated with semaglutide is gastrointestinal in nature (nausea and vomiting). No significant differences were observed between semaglutide and comparator groups. (See Figure 1)

Conclusion:
Semaglutide appears to have a favorable safety profile across diverse patient populations and treatment durations, supporting its continued use in the management of type 2 diabetes mellitus and obesity. It is generally well-tolerated, with a low incidence of adverse events. Clinicians should be aware of these findings and monitor patients accordingly. Further long-term studies are warranted to assess the safety of semaglutide in clinical practice.
Abstract 4134333: Blood pressure reduction in diabetic patients with resistant hypertension: results from the aprocitentan PRECISION study
Authors: Flack John , Bakris George , Dreier Roland , Sassi-Sayadi Mouna , Schlaich Markus , Wang Jiguang , Weber Michael , Narkiewicz Krzysztof
Published: November 2024

Background:
In patients with resistant hypertension (RHT), diabetes is a frequent comorbidity that increases the risk of cardiovascular events. The phase-3 PRECISION study demonstrated the efficacy of aprocitentan (APRO), a dual endothelin ET
A
/ET
B
receptor antagonist, to lower blood pressure (BP) in patients with RHT. In this pre-planned PRECISION post hoc analysis, we evaluated the BP lowering effect of APRO in diabetic patients.

Methods:
Eligible patients were hypertensive despite treatment with ≥3 antihypertensive medications from different classes. After ≥4 weeks of combination therapy (amlodipine/valsartan/hydrochlorothiazide), patients still hypertensive received single-blind placebo for a run-in period, followed by a 4-week double-blind part (APRO 12.5 mg, 25 mg, or placebo), a 32-week single-blind part (APRO 25 mg) and a 12-week double-blind withdrawal part (APRO 25 mg or placebo). The primary endpoint was change from baseline to Week 4 in mean trough office SBP.

Results:
Out of 730 patients, 395 (54%) had diabetes (APRO 12.5 mg, n=112; 25 mg, n=107; placebo, n=116).

At Week 4, APRO reduced office SBP (12.5 mg: −14.6; 25 mg: −14.1 mmHg) vs placebo (−9.4 mmHg) in diabetic patients, with no treatment/diabetes status interaction (p=0.77). The reduction was maintained at Week 36 (−16.2 mmHg). APRO also reduced mean 24-hour ambulatory SBP at Week 4 (12.5 mg: −7.4 mmHg; 25 mg: −9.5 mmHg) vs placebo (−2.2 mmHg), most pronounced on night-time values (12.5 mg: −8.9 mmHg; 25 mg: −13.1 mmHg; placebo: −1.6 mmHg).

At Week 40, after 4 weeks of withdrawal, office SBP increased in placebo patients (+3.6 mmHg) and remained stable with APRO 25 mg (+0.2 mmHg).

A substantial reduction in urine albumin–creatinine ratio of 33% and 37% was observed at Week 4 for APRO 12.5 mg and 25 mg, respectively, compared with an increase of 11% for placebo.

Edema/fluid retention were the most common adverse events; they were mild-to-moderate in most cases and dose dependent (9%, 23%, and 2% of patients receiving APRO 12.5 mg, 25 mg, and placebo, respectively, up to Week 4). During the study, 11 patients were hospitalized for heart failure (10 treated with APRO 25 mg and one with placebo). Among these, 6 had chronic kidney disease stage 3–4, and 5 had medical history of heart failure; no cases were fatal.

Conclusion:
APRO produced clinically relevant and sustained BP reduction in diabetic patients with RHT, consistent with the effect observed in the overall population.
Abstract 4135655: Gender Differences in Invasive Angiography and Early Revascularization after Coronary Computed Tomography Angiography
Authors: Lee Alexander , Gransar Heidi , Hayes Sean , Friedman John , thomson louise , Dey Damini , Asif Anum , Bairey Merz C Noel , Wei Janet , Gulati Martha , Berman Daniel , Han Donghee
Published: November 2024

Background:
Coronary CT angiography (CCTA) has emerged as a first line tool for detecting CAD and assessing need for invasive coronary angiography (ICA). Historically, women have higher cardiovascular mortality compared to men with similar coronary plaque burden, yet remain undertreated. This study aims to investigate gender differences in ICA rates and subsequent revascularization following CCTA.

Methods:
This study included adults who underwent CCTA between 2013-2019 at a single institution. CCTA stenosis severity was categorized as <50%, 50-69% and ≥70%. Plaque burden was assessed by segment involvement score (SIS), defined as number of coronary segments with plaque. Outcomes included ICA and revascularization within 90 days of CCTA. Multivariable logistic regression analysis was performed after adjustment for demographic, clinical, and imaging variables.

Results:
Of 5,855 patients (mean age 61 years, 58% men) who underwent CCTA, 582 (9.9%) and 386 (6.6%) underwent ICA and revascularization, respectively. There was no significant difference in ICA rates between men and women with similar CCTA stenosis severity (
Figure 1A
; stenosis 50-69%: 17.9% vs. 19.2%, p=0.677; stenosis ≥70%: 53.8% vs. 58.3%: p=0.313). However, among patients with stenosis ≥70% who underwent ICA, men had significantly higher rates of revascularization (
Figure 1A
. 80.1% vs. 69.2%, p=0.029). In multivariable analysis, male gender was an independent predictor of revascularization after adjustment for clinical characteristics, including CCTA stenosis severity and SIS (male gender: OR 1.58, 95% CI: 1.01-2.47, p=0.047). Of note, in patients with stenosis ≥70%, rates of revascularization in women were significantly lower in the early study period (years 2013-2015, p=0.020); however, the difference narrowed in the recent study period (years 2016-2019, p=0.309) (
Figure 1B)
.

Conclusion:
There were comparable ICA rates between men and women. Women with severe stenosis (≥70%) by CCTA had significantly lower rates of revascularization, particularly in the early study period. These findings suggest a disparity in the management of CCTA-identified severe CAD, though it has demonstrated improvement in recent years.
Abstract 4136900: Left-to-right ventricular volume ratio as a predictor of cardiovascular events: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Hoballah Malak , Chehab Omar , Abdollahi Ashkan , Wu Colin , Scarpa Bruna , Post Wendy , Allen Norrina , Bluemke David , Ambale-Venkatesh Bharath , Lima Joao AC
Published: November 2024

Background:
The left ventricle (LV) and right ventricle (RV) are closely connected anatomically and functionally. Therefore, relative volume alterations signify pathologic disequilibrium even when within the normal range for chamber volumes. We aimed to define the prognostic value of volumetric imbalance between the LV and RV in the general population.

Methods:
The study sample consisted of 4073 asymptomatic participants from the Multi-Ethnic Study of Atherosclerosis who had a cardiac MRI at baseline. The left to right ventricular volume ratio (LRVR) was defined as LV volume/RV volume at end diastole. LRVR was categorized into balanced reference category 0.8-1.3, low (RV predominance) <0.8, and high (LV predominance) >1.3. Multivariable cox regression models were used to study the association between LRVR and heart failure (HF), atrial fibrillation (AF), and death.

Results:
The mean age of participants was 61.3±10 years, with 52% females. Participants were followed for a median of 17.8 years for HF, 16.7 years for AF, and 17.1 years for death. During follow up, 239 (5.9%) participants developed HF, 772 (19%) developed AF, and 906 (22.2%) died. When compared with the reference balanced LRVR group, those with high LRVR had increased risk of HF (HR 2.55; 95% CI 1.7-3.8; p <0.01), AF (HR 1.57; 95% CI: 1.2-2.06; p<0.01), and death (HR 1.63; 95% CI: 1.29-2.07; p<0.01) after adjusting for demographics and traditional cardiovascular risk factors. Participants with low LRVR had increased risk of HF (HR 1.88; 95% CI 1.1-3.2; p=0.02) and death (HR 1.51; 95% CI 1.12-2.04; p<0.01) in crude models. Adjusting for risk factors maintained increased risk of HF and death, but statistical significance was lost. Low LRVR was not associated with increased risk of AF. In a subgroup of participants with both absolute RV and LV volumes within normal ranges, high LRVR was still associated with increased risk of HF, AF, and death after adjusting for risk factors.

Conclusion:
In healthy asymptomatic participants at baseline, LV volume exceeding RV volume by at least 30% is associated with increased risk of HF, AF, and death. This relationship is independent of cardiovascular risk factors and absolute dilatation of either ventricle.
Abstract 4136932: Impact of Different Socioeconomic Metrics on Heart Failure-Related Admission and Short-Term Outcomes in Maryland
Authors: Akinyemi Oluwasegun , Odusanya Eunice , Fasokun Mojisola , Weldeslase Terhas , Ugwendum Derek , Lasisi Oluwatobi , Cadet Nadia , Ogundipe Temitayo , Michael Miriam
Published: November 2024

Introduction:
Annually, over 500,000 Americans are hospitalized due to heart failure (HF), marking it as a major contributor to morbidity and mortality. It also poses a significant financial burden and leads to considerable losses in productivity.

Objective:
This study investigates the predictive accuracy of different socioeconomic metrics on the risk and outcomes of HF in Maryland.

Methodology:
A retrospective analysis of the Maryland State Inpatient Database (2016-2020) was conducted to assess the predictive accuracy of race/ethnicity, insurance status, household median income, and neighborhood poverty level (measured by the Distressed Communities Index) on the risk of heart failure-related hospital admissions and outcomes. Multivariate logistic regression models were also used to adjust for confounders.

Result:
During the study period, a total of 389,220 cases of HF were reported in the Maryland SID. The majority of these patients were white (56.8%) and female (51.1%), with a median age of 73 years (interquartile range [IQR] 62-82 years). The in-hospital mortality rate was 5.1%, while rates of atrial fibrillation, cardiac arrest and prolonged hospital stay were 34.4%, 0.3%, and 48.4%, respectively. Multivariate analysis revealed a substantial area under the ROC curve (AUC) indicating good model performance: 0.88 for predicting HF, 0.64 for atrial fibrillation, 0.64 for cardiac arrest 0.57 for prolonged hospital stays, 0.63 for mortality. Subgroup analyses showed variable predictiveness by race (AUC = 0.4378), payment method (AUC = 0.5754), income quartile (AUC = 0.5202), and deprivation composite score (AUC = 0.4751). Patients with private insurance had the highest risk of stress cardiomyopathy (odds ratio [OR] = 1.98; 95% confidence interval [CI] 1.70-2.29). Socioeconomic metrics, including neighborhood distress, showed varying predictive accuracy for the HF-related admissions and selected short-term outcomes, with the highest predictive accuracy for neighborhood distress on the risk of HF (AUC = 0.50, std: 0.006), atrial fibrillation (AUC = 0.48, std: 0.0007), cardiac arrest (AUC = 0.51, std: 0.007), and prolonged hospital stays (AUC = 0.53, std: 0.0005) and mortality (AUC = 0.50, std: 0.0015).

Conclusion:
Neighborhood poverty level demonstrates significant predictive power for assessing the risk of HF-related hospital admissions and the short-term outcomes among Maryland residents, exceeding factors like insurance and race/ethnicity.
Abstract 4136963: Long-term Effects of Continuous Positive Airway Pressure on Cardiovascular Outcomes after Acute Myocardial Infarction in Obstructive Sleep Apnea Patients
Authors: Khosa Jaskiran , Adam Ahmad , Madhwala Amina , Lin Jane , shi jiaxiao , Hwang Dennis , Ren Jie
Published: November 2024

Background:
There is increasing evidence of a strong association between obstructive sleep apnea (OSA) and ischemic heart disease. Previous studies have demonstrated OSA to be a significant predictor of incident CAD, while recent studies have confirmed individuals with OSA to have 3.9 times greater incidence of major adverse cardiac and cerebrovascular events (MACCE) at one year following acute myocardial infarction (AMI) than individuals without OSA. Whether treatment with continuous positive airway pressure (CPAP) after AMI in OSA patients reduces MACCE is not known. This study investigated the long-term cardiovascular outcomes associated with CPAP therapy after AMI in OSA patients, and is the first study to evaluate the effect of CPAP on secondary prevention after AMI.

Methods:
This retrospective study was conducted from 2015 to 2019 and included adults with AMI. Patients with at least moderate OSA (n=180) were followed for at least 1 year and categorized as either AMI and compliant to CPAP (54 patients) or AMI and non-compliant to CPAP (126 patients). We estimated the incidence of MACCE (early rehospitalization, re-catheterization, CABG, recurrent MI, CHF, arrhythmia, stroke, and death) in each group during follow-up from the index event. Continuous and categorical variables were analyzed for significance with Wilcoxon’s test and Fisher’s exact test respectively. Multivariate analyses were performed to adjust for confounders.

Results:
Most participants were male, the average age was 66 years old, and no significant demographic difference was identified between the two groups. Compared with non-compliant patients, CPAP-compliant patients exhibited significantly lower overall MACCE incidence (22.2% vs 40.5%, p=0.03) and repeat catheterization rate (1.9% vs 11.1%, p=0.04) after AMI.

Conclusion:
Long-term, compliant CPAP therapy, as compared with non-compliant CPAP therapy, significantly reduces recurrent cardiovascular events and provides effective secondary prevention after AMI in patients with at least moderate OSA.
Abstract 4136996: Co-morbid Insomnia and Obstructive Sleep Apnea (COMISA) are Related to Incident Hypertension in a 20-Year Retrospective Cohort Study of 1.3 million Younger Men and Women Veterans: Associations by Sex
Authors: Gaffey Allison , ZINCHUK ANDREY , Yaggi Henry , brandt cynthia , Haskell Sally , Burg Matthew
Published: November 2024

Introduction:
Insomnia and obstructive sleep apnea (OSA) each increase risk for hypertension (HTN). Among older adults, there is a negative synergistic association of comorbid insomnia and OSA (i.e., COMISA) on incident cardiovascular disease (CVD) but it is unknown if this comorbidity is associated with HTN risk earlier in the lifespan.

Research Questions:
1) Is COMISA associated with incident HTN among younger adults? 2) Do COMISA-HTN associations differ by sex?

Hypotheses:
We hypothesized that 1) COMISA would be associated with a greater risk of HTN than having no sleep disorder, 2) the hazard would be larger than for insomnia and OSA alone, and 3) distinct COMISA-HTN associations would be observed among men and women, respectively.

Methods:
Analyses included Veterans who enrolled in Veterans Health Administration (VA) care 2001-2021, a group selected because of its early adult age distribution. We merged administrative data, including outpatient and inpatient encounters, diagnoses, (ICD-9-CM/10 codes/dates) and pharmacy records. Veterans without demographic data, a history of other sleep disorders or CVD, or <2 clinical encounters were excluded. Sleep disorders were defined by 1 inpatient or ≥2 outpatient encounters. HTN was defined by 1 inpatient or ≥2 outpatient encounters and/or ≥1 antihypertensive medication fill. Time-varying Cox proportional hazard models were adjusted for sociodemographic, behavioral/lifestyle, and clinical factors, and stratified analyses by sex. We used multiple imputation to address missing data.

Results:
Analyses included 1,293,165 Veterans (12% women; mean age 32.8) with an average follow-up of 7.6 years. Men with COMISA showed a 19% greater risk of HTN vs. no sleep diagnosis (95% CL: 1.17-1.20). Risks were slightly lower – but still significant – for men with only insomnia (HR:1.08 [95% CL: 1.06-1.09]) or only OSA (HR:1.15 [95% CL: 1.13-1.16]). Women with COMISA had a 21% greater risk of HTN vs. those without a sleep diagnosis (95% CL: 1.16-1.26), and those with insomnia (HR:1.15 [95% CL: 1.11-1.19]) or OSA (HR:1.13 [95% CL: 1.09-1.17]) showed a lower, though still significant risk.

Conclusion:
In this younger group, Veterans with COMISA had a 19-21% greater risk of HTN than without a disorder, and this risk was similar by sex and slightly higher than that attributable to insomnia or OSA alone. Increased identification of disordered sleep among younger adults should be a cardiovascular prevention priority.
Abstract 4139115: Genomic, Phenomic, and Geographic Relationships with Leukocyte Telomere Length in the U.S. Yields New Insights for Neoplasms and Cardiometabolic Disease
Authors: Nakao Tetsushi , Koyama Satoshi , Truong Buu , Uddin Md Mesbah , Misra Anika , Patel Aniruddh , Vlasschaert Caitlyn , Bick Alexander , Codd Veryan , Samani Nilesh , Hornsby Whitney , Ellinor Patrick , Natarajan Pradeep
Published: November 2024

Background:
Leukocyte telomere length (LTL) is an age-related marker strongly associated with neoplasms and cardiometabolic disease. LTL is also intimately linked with clonal hematopoiesis of indeterminate potential (CHIP), a recently described risk factor for cardiovascular disease (CVD). However, population-scale investigations of LTL in diverse backgrounds are limited, and geolocational variance has not been studied.

Method:
LTL and CHIP were derived using blood-derived whole genome sequencing data from 244,819 diverse U.S. residents in the NIH All of Us Research Program (AoU). We performed association analyses of LTL with CHIP and other available health-related traits, Phecode, as well as geolocation data by ZIP code. Genome-wide association study (GWAS) of LTL in AoU and meta-analysis with UK Biobank were performed. All association tests were adjusted for age, sex, sequencing site, and the first 10 genetic principal components with multiple test corrections. Mediation analysis was adjusted for additional risk factors for CVD.

Result:
Among 244,819 AoU participants, 146,717 (59.9%) were female with mean (standard deviation) age 51.8 (±16) years. Estimated LTL correlated strongly with age, sex, and genetic ancestry in AoU. Socioeconomic status, lifestyle variables, anthropometry, blood biomarkers (e.g., lipids and glucose), and vital signs were associated with LTL in AoU. Phecode analysis showed LTL is associated with neoplasms and age-related conditions, including CVDs. LTL mediated some of the observed increased coronary artery disease risk among individuals with hematologic malignancies (
P
< 2 × 10
-16
). Significantly longer LTL clustered in the West Coast and Central Midwest (
P
= 0.001 and 0.033, respectively), while significantly shorter LTL clustered in the Southeast (
P
= 0.001) (Figure). GWAS meta-analyses identified 197 loci, of which 36 (18%) were novel, including ancestry-specific loci. Rare variant aggregation test found 9 novel associated genes.

Conclusions:
LTL is a marker of biological age that is associated and interacts with neoplasms, CVDs, and its various risk factors, with notable geographic variability within the U.S. Germline genetic analyses of LTL yield new insights into drivers of LTL.
Abstract 4139135: Trends in Stroke Related Mortality in Atrial Fibrillation Patients Aged 25 and Older in the United States: Insights from the CDC WONDER Database
Authors: Naveed Muhammad Abdullah , Omer Rehan Muhammad , Ali Ahila , Iqbal Rabia , Azeem Bazil , Akbar Usman , Gonuguntla Karthik , Khan Muhammad , sattar yasar , Asad Zain Ul Abideen , balla sudarshan , Munir Bilal
Published: November 2024

Background:
Stroke associated with atrial fibrillation (AF) is a significant cause of mortality. This CDC analysis delves into mortality trends due to stroke in AF patients aged ≥ 25 years, from 1999 to 2020. By analyzing extensive datasets we scrutinized how factors such as gender, race, region of residence, and level of urbanization intersect with mortality rates.

Methods:
Death data from 1999 to 2020 was analyzed using the Centers for Disease Control and Prevention database, employing ICD codes I48 for AF and I64 for stroke. Age-adjusted mortality rate (AAMR) per 100,000 people with 95% confidence intervals was calculated for the total population, stratified by gender, race, urban/rural status, and census region. The Joinpoint regression software was used to calculate annual percentage change (APC) trend for each stratification.

Results:
In the U.S. between 1999 and 2020, total of 331,106 deaths occurred among adults due to AF associated with stroke. Deaths occurred predominantly in medical facilities (43.2%). The overall AAMR for AF associated stroke decreased from 26.8 per 100,000 in 1999 to 18.4 in 2020, with an AAPC of -2.05 (p value < 0.000001). Additionally, AAMR declined significantly from 1999 to 2018 (APC: -2.65, p value = 0.012398), followed by an increase from 2018 to 2020 (APC: 3.90, p value = 0.220356). Women had slightly higher AAMRs compared to men (men: 6.6; women: 7.1). The AAMR for women reduced substantially from 1999 to 2020 than for men. AAMRs varied among racial/ethnic groups, with White patients having the highest AAMR (7.4), followed by Blacks (5.4), American Indian or Alaska Natives (4.6), Asian or Pacific Islanders (4.5), and Hispanic population (4.1). AAMRs decreased for all races except for Black population. Geographically, AAMRs ranged from 4.3 in Nevada to 11.9 in Vermont, with the Western region showing the highest mortality (AAMR: 7.9). Nonmetropolitan areas had slightly higher AAMRs than metropolitan areas, with both experiencing a decrease over the study period.

Conclusion:
This analysis depicts significant disparities in mortality rates attributed to stroke associated with AF and underscores the need for larger population-based studies to further understand the primary factors influencing the observed geographical, racial, and gender differences. Targeted interventions and equitable healthcare access are crucial to mitigate these disparities and improve outcomes for this population.
Abstract 4139148: Mechanisms of Maternal Cardiovascular Disease Development in a Novel Mouse Model of Pregnancy-Induced Diabetes
Authors: Badmus Olufunto , Taylor Erin , Arthur Gertrude , Taylor Lucy , McGowan Karis , Wasson Andrew , Cucolicchio Isabela , Stec David
Published: November 2024

Background:
Women with gestational diabetes mellitus (GDM) are more likely to develop cardiovascular disease (CVD) within 3 to 10 years following pregnancy. Endothelial dysfunction is a mechanism implicated in both hyperglycemia and CVDs, and it may constitute the missing link in this interaction. One reason for the lack of progress into the cardiovascular complications of GDM is the need for appropriate preclinical models that mimic human GDM. Also, the exact mechanisms mediating increased future cardiovascular risk in maternal with pregnancy-induced diabetes is unclear.

Aim:
To determine the mechanisms underlying cardiovascular disease in hormonal model of GDM.

Methods:
Sixteen week-old C57BL/6J female mice were treated with insulin receptor antagonist (S961) or saline (n=4) from the second trimester of pregnancy until delivery to develop a model of GDM. Glucose tolerance test was determined by glucometer and fasting insulin by colorimetry. Cardiac structure and function were measured by echocardiography (VEVO 3100) and pulse wave velocity was measured by Pulse Wave Doppler. Exercise tolerance test was performed on treadmill. Plasma endothelin-1 and nitrite were measured by ELISA and colorimetric assay. Aortic SIRT-1 was determined by western blot and aortic vascular reactivity was determined by wire myograph.

Results:
S961-induced GDM mice exhibit hyperglycemia (169.2 ± 3.6 vs. 105.5 ± 10.8mg/dL,
P<0.004
) and hyperinsulinemia (1.9 ± 0.2 vs. 0.8 ± 0.1ng/ml
, p<0.01
) which mimics the condition observed in human GDM. Interestingly, S961-induced GDM mice went on to develop systolic and diastolic dysfunction, vascular stiffness (3.7 ± 0.1 vs. 3.1 ± 0.08m/s,
p<0.005
), exercise intolerance and increased thickness of the cardiac wall at 10 weeks post-delivery. Plasma ET-1 was elevated in our model during pregnancy (28.1 ± 1.7 vs. 5.2 ± 0.2pg/ml,
p<0.002
) and at 10 weeks post-delivery (19.9 ± 2.9 vs. 6.7 ± 0.7pg/ml,
p<0.05
). Circulating NO and aortic expression of sirtuin-1 (SIRT 1), that is involved in endothelial longevity is reduced in GDM mice. Additionally, vascular relaxation to acetylcholine was attenuated in S961-induced GDM mice.

Conclusion:
We have developed a novel mouse model of GDM similar to that observed in pregnant women by treatment with S961. Moreover, S961 treated mice develop cardiac dysfunction and vascular stiffness at 10 weeks post-delivery. Alterations in ET-1, SIRT 1, and NO levels may be responsible for the development of CVD in this model.
Abstract 4139177: Five-Year Clinical Outcomes of Balloon-Expandable versus Self-Expanding Transcatheter Aortic Valve Replacement in Patients with Small Aortic Annulus
Authors: Pawar Shubhadarshini , Patel Vivek , NAGASAKA TAKASHI , Basantes Jair , Madaan Prateek , Markel Justin , Koren Ofir , Patel Dhairya , Chakravarty Tarun , Nakamura Mamoo , Cheng Wen , Skaf Sabah , Al-Jilaihawi Hasan , Makkar Raj , Gupta Aakriti
Published: November 2024

Introduction:
Self-expanding transcatheter aortic valves (SEV) have reportedly better hemodynamic outcomes, and similar clinical outcomes compared to balloon-expanding valves (BEV) at 1 year in patients with a small aortic annulus based on results from the SMART trial. Head-to-head comparison of long-term clinical outcomes, however, is lacking.

Objectives:
To compare the long-term (5 years) echocardiographic and cardiovascular outcomes in BEV versus SEV in patients with small aortic annulus undergoing transcatheter aortic valve replacement (TAVR).

Methodology:
The RESOLVE registry included consecutive patients who underwent TAVR and survived up to 30 days at Cedars-Sinai Medical Center with either BEV or SEV from 2015 to 2020, with clinical variables obtained from the STS/TVT registry. CT core lab analysis identified patients with a small aortic annulus (<430 mm
2
), who were systematically followed up with clinical exams and echocardiography until December 2023. The primary outcome was a composite of all-cause mortality, stroke or transient ischemic attack, or heart failure hospitalization at 5 years.

Results:
Out of 1392 patients, a total of 423 met criteria for small aortic annulus (345 BEV, 78 SEV), with a median follow-up of 5 years (4-6 years). There were no significant differences in baseline sociodemographic and clinical characteristics between the BEV and SEV groups. (Figure 1) The post-TAVR invasive aortic valve mean gradient were similar in both groups [Median (IQR): BEV:3(1-5.8), SEV: 3.4(0.4-6.6), p 0.58], while echocardiographic gradients were higher in BEV group [Median (IQR): BEV:12 (9-15), SEV:8(6-11), p<0.001)].There was no significant difference in primary outcome at 5 years in Cox multivariable regression analysis (HR:1.21, 95% CI 0.81-1.82, p 0.33) (Figure 2). There were no significant differences in other clinical endpoints at 5 years, although patients with SEV had lower echocardiographic gradients and higher indexed effective orifice area. (Figure 2-3)

Conclusion:
Post-TAVR invasive aortic valve gradients were similar between BEV and SEV, despite higher echocardiographic transaortic gradients in BEV patients. We found no significant difference in 5-year clinical outcomes between patients who received TAVR with BEV or SEV.
Abstract 4139179: Is Prenatal Diagnosis Responsible for Differences in Timing to Postnatal Intervention for Critical Congenital Heart Defects?
Authors: Woo Joyce , Gotteiner Nina , Anderson Brett , Yee Lynn , Grobman William , Davis Matthew , Laternser Christina
Published: November 2024

Introduction:
The relationships between prenatal diagnosis of congenital heart defects (CHDs) and outcomes are inconsistent. Some studies have shown that compared to postnatal diagnosis, prenatal diagnosis is associated with later surgical timing and worse outcomes. These findings could be due to confounding because more severe CHDs are likelier to be diagnosed on prenatal ultrasonography. To bypass this confounding, we evaluated prenatal diagnosis as a mediator.

Aim:
To evaluate whether prenatal diagnosis of CHD mediates the association between disease severity and timing to postnatal intervention.

Hypothesis:
Infants with severe CHD receive intervention sooner than those with mild CHD
due to
a higher prenatal diagnosis prevalence.

Methods:
This is a retrospective cohort study of all infants who received their initial cardiac catheterization or surgery between 0-60 days (i.e., critical CHD) at Ann&Robert H. Lurie Children’s Hospital of Chicago (2015-2021). Birthing individuals with inadequate prenatal care were excluded. The primary exposure variable was a three-level categorical variable derived from existing literature, categorizing disease severity based on anatomic factors (mild, moderate, and severe CHD). The outcome was age at intervention, i.e., cardiac catheterization or surgery, whichever occurred sooner, in days. The mediator variable was whether prenatal diagnosis occurred. Control variables included birth weight, sex, surgery during the COVID-19 pandemic, race, ethnicity, birth hospital’s level of perinatal care as designated by Illinois state, presence of a syndrome or non-cardiac abnormality, and insurance status.

Results:
In total, 429 parent-infant pairs met inclusion criteria; 68.3% had prenatal diagnosis and 28.4% had severe CHD. In adjusted analyses, compared to those with the mild CHD, those with moderate CHD had 40.0% higher probability of prenatal diagnosis (p<0.001) and on average, received intervention 14 days sooner (p=0.001). Those with severe CHD had a 59.5% higher probability of prenatal diagnosis (p<0.001), and on average received intervention 19 days sooner (p<0.001). In a mediation analysis, prenatal diagnosis accounted for 27.2% of the difference in surgical timing between moderate and mild disease, and 29.5% of the difference in surgical timing between severe and mild disease (
Figure 1
).

Conclusion:
The relationship between CHD severity and timing to postnatal intervention is partly attributable to prenatal diagnosis.
Abstract 4139186: Bempedoic Acid and Limb Outcomes in Statin-Intolerant Patients with Peripheral Artery Disease
Authors: Bonaca Marc , Canonico Mario Enrico , Li Na , Sasiela William , Nissen Steven , Lincoff Abraham , Nicholls Stephen
Published: November 2024

Introduction:
Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALE) and CV events and have high rates of recurrence of these events. Recently, bempedoic acid was shown to reduce MACE in primary and secondary prevention patients. Whether bempedoic acid reduces the risk of MALE is unknown.

Methods:
CLEAR Outcomes randomized 13,970 patients to bempedoic acid 180 mg or placebo. A clinical history of PAD was reported by investigators at baseline. Two blinded vascular medicine specialists independently adjudicated all adverse events for limb outcomes including worsening PAD symptoms leading to revascularization, chronic limb threatening ischemia, and acute limb ischemia events with the composite defined as MALE. Outcomes were assessed as time to first event as well as total (including recurrent) events using a negative binomial approach.

Results:
A total of 1,624 of the enrolled patients had PAD at baseline. Over a median of 41.1 months the rate of first and total MALE events in patients with PAD in the placebo group were 8.3% and 13.7% respectively. Bempedoic acid reduced first MALE events by 36% (HR 0.64, 95% CI 0.44-0.93) with an absolute risk reduction (ARR) of 2.5% and number needed to treat (NNT) of 40, compared to placebo (figure, panel A). Similarly, when considering total events, bempedoic acid reduced MALE by 45% (RR 0.55, 95% CI 0.35 – 0.85, figure panel b). Consistent benefits were observed for MALE in the overall population as well as composites of MACE and MALE in both populations (Figure panel b). There was no evidence of effect modification for the benefit of bempedoic acid for MALE on the basis of PAD at baseline (p-interaction 0.09).

Conclusions:
Bempedoic acid significantly reduces MALE. Benefits appear potentially greater when considering total (i.e. recurrent) events. These findings support the importance of LDL-C lowering therapy in patients with PAD. In addition, these findings support the early use of therapies with proven MALE benefit, including bempedoic acid, to optimize outcomes in PAD.
Abstract 4139187: Electrophysiological and Mechanical Characterization of Human Ventricular Myocardium from Patients with Primary or Secondary Cardiac Hypertrophy
Authors: Santini Lorenzo , Pioner Jose Manuel , Ferrantini Cecilia , Palandri Chiara , Giammarino Lucrezia , Musumeci Monica , Tesi Chiara , Cerbai Elisabetta , Poggesi Corrado , Coppini Raffaele
Published: November 2024

Left-ventricular hypertrophy (LVH) is an adaptive condition to hemodynamic stress often involving the left ventricle (LV). This pathological condition is associated with clinical complications such as ventricular arrhythmias and diastolic dysfunction, the molecular and cellular mechanisms of which have been poorly investigated in the human heart.

We collected myocardial samples from the upper interventricular septum of 132 patients with hypertrophic cardiomyopathy (HCM), 42 patients with aortic stenosis and severe LVH (AoS-LVH) and 12 non-failing non-hypertrophic patients with valve disease (NF-NH), who underwent myectomy operations at our cardiac surgery center. Samples were used to isolate single viable cardiomyocytes from the left ventricle to perform patch-clamp electrophysiological studies and intracellular calcium measurements with fluorescent dyes. Intact trabeculae were also dissected to perform isometric force measurements of electrically-stimulated twitches.

Single-cell patch-clamp studies revealed a marked prolongation of action potential duration (APD) in HCM (N=82, mean APD at 90% repolarization=763±252ms at 0.5Hz) and AoS-LVH (N=22, APD90%=579±147ms) samples with respect to NF-NH (N=12, APD90%=447±88ms). In both HCM and AoS-LVH cardiomyocytes, APD prolongation was associated with increased late-Na
+
current with respect to NF-NH, while L-type Ca
2+
current was enlarged only in HCM samples. Ca
2+
-fluorescence studies revealed markedly slower Ca-transient (CaT) kinetics in myocardial samples from HCM (N=38, mean CaT 50% decay time at 0.5 Hz = 658±179ms) and AoS-LVH patients (N=9, CaT50%= 568±187ms), when compared with NF-NH samples (N=8, CaT50%=283±59ms), paralleled by elevated diastolic [Ca
2+
]. Twitch force measurements in intact trabeculae revealed prolonged isometric contractions in HCM (N=78, overall twitch duration at 0.5Hz= 730±147ms) and in AoS-LVH patient-samples (N=24, TwD=669±116ms), as compared with NF-NH (N=7, TwD=511±73ms). Force-frequency relationship was flat in pathological samples, while NF-NH trabeculae showed a clear increase in twitch amplitude while increasing pacing rate to 2Hz.

Our results suggest that the main features of functional cardiomyocyte remodeling (that is, changes in the expression and/or function of ion-channel and EC-coupling proteins) are qualitatively similar in primary vs. secondary LVH, albeit abnormalities are quantitatively more extensive in HCM samples.
Abstract 4139191: ETX-258 - A GalOmic™ siRNA for the Treatment of Heart Failure Following Myocardial Infarction
Authors: Fischer Alexander , Pursell Natalie , Whitmore Alan
Published: November 2024

Introduction:
Heart failure with reduced ejection fraction (HFrEF) remains a significant clinical challenge, evidenced by high hospitalization rates and five-year mortality. Current treatments are limited by side effects, poor patient compliance, and the necessity for gradual drug titration. These challenges highlight the need for new therapies that are both safe and effective in targeting the structural remodeling pivotal to disease progression post-myocardial infarction (MI). e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. This highly specific mechanism of action limits unwanted side effects, positioning it as a promising approach to HFrEF treatment.

Methods:
Potent siRNAs against a hepatic target with cardioprotective potential were designed
in silico.
Candidate siRNAs were screened
in vitro
in HEK293 cells and
in vivo
in C57BL/6J mice to select the lead GalOmic™ siRNA, ETX-258. MI was induced by ligation of the left anterior descending artery in C57BL/6J mice after which ETX-258 was injected subcutaneously weekly for 6 weeks. Eplerenone, a mineralocorticoid receptor antagonist which is part of the current treatment regimen for HFrEF, was used as a comparator. Cardiac function was assessed by echocardiography at 2-, 4- and 6-weeks post-MI. Cardiac damage and structural remodeling were evaluated using circulating biomarkers of cardiac function and histological assessment.

Results:
ETX-258 was selected as a highly active siRNA for the treatment of heart failure with a long duration of action. Post-MI treatment with ETX-258 significantly improved key echocardiographic parameters of cardiac function, including ejection fraction and total cardiac output, achieving results comparable to eplerenone. Additionally, both structural cardiac parameters and markers of damage and remodeling showed significant improvements, reaching similar levels in both ETX-258 and eplerenone-treated mice.

Conclusions:
High unmet need remains for HFrEF patients despite existing therapies. These results highlight the potential of ETX-258 to improve cardiac function and pathogenic structural remodeling post-MI. This, paired with the long duration of action and favorable safety profile of GalOmic™ siRNAs, makes ETX-258 a promising candidate for further clinical development.
Abstract 4139192: Remote monitoring platform improves communication and clinical decision making for pediatric interstage healthcare team members
Authors: Erickson Lori , Ricketts Amy , ELLIOTT Melissa
Published: November 2024

Background:
Asynchronous remote patient monitoring (RPM) is increasingly common in healthcare models for infants with congenital heart disease (CHD). Using a downloadable mobile application with a software platform like CHAMP App
®
allows parents to proactively engage in data entry, providing pediatric healthcare teams (HCT) timely information without relying solely on parent messaging or calls.

Research Question:
How does the use of RPM impact family communication and clinical decision-making experiences for HCTs?

Goals:
To identify the HCT’s experience through a secondary review of the CHAMP Cardiac Repository, using parent-entered interstage data from home for infants with CHD.

Methods:
This retrospective multi-institution cohort (Table 1) spanned from 5/2019-8/2023, collecting HCTs feedback via Likert responses (Table 2) about experiences with infant monitoring endpoint, which were analyzed in SPSS.
Results:
Response rates of 75.8% (493/650) were achieved across 10 pediatric cardiac care centers. HCTs reported improved communication (4.5
+
.77) and clinical decision-making with video reviews (4.47
+
.79). Parents' data engagement averaged 268
+
195.3 total points (oxygen saturation, weights, and/or videos) per infant. Higher engagement correlated with better HCT communication (p <.001) and decision-making (p <.0001), both with small effect sizes. Improved clinical decision-making was noted in families who used study-provided iPads for video recordings (mean score 4.63 ± 0.84) compared to those using personal devices (mean score 4.42 ± 0.734, p = .03), with 69.2% using personal devices.

Conclusions:
In this modern cohort, families engaged well with data entry through a remote monitoring platform, and HCTs reported significant improvements in communication with families for their child’s data from home and clinical decision-making after reviewing videos. Future research should explore barriers to mobile data engagement and assess HCT preferences for video review.
Abstract 4139194: Predicting Cholesterol Screening Behavior After Age 50 Using Machine Learning: Insights from the Health and Retirement Study
Authors: Kuo Wan-Chin , Chen Jingyu , McDonald Anthony , Chang Jui-Hung , Johnson Heather
Published: November 2024

Background:
In the U.S., about 8% of adults never received cholesterol screening. Although machine learning (ML) has been used to develop decision tools for Atherosclerotic Cardiovascular Disease (ASCVD) risk prediction, its application in behavioral forecasting has not yet been explored in the context of cholesterol screening behaviors. This study aimed to examine the performance and accuracy of ML algorithms in forecasting cholesterol screening behaviors in adults after age 50.

Methods:
This analysis used deidentified data from the Health and Retirement Study (HRS) 2004-2018. HRS is a longitudinal survey among 23,000 households in the U.S. Participants were excluded from the current analysis if they passed away by 2019, ever had ASCVD or stroke, were under age 50 at baseline, or had missing data in self-reported cholesterol screening. In total, 7176 participants (mean age [SD]=62 [8]) met the inclusion criteria; participants were randomly split into a training set (80%) and a testing set (20%). The synthetic minority oversampling technique was used to solve the imbalance distribution of the rare event. Five ML algorithms were used: random forest, gradient boosting machine (GBM), XGBoost, Support Vector Machine (SVM), and logistic regression. Accuracy, AUROC, and positive predictive value (PPV) were used to compare model performance. The average gain was evaluated for feature importance in the demographic and health domains.

Results:
In total, 232 (3.2%) respondents did not receive any cholesterol screening from 2008 to 2018. Experiments with five ML algorithms suggested that XGBoost with deeper trees and learning rate performed better in classifying those who did not screen for cholesterol levels over 10 years. Adding prior cholesterol screening history (2004-2006) into the model significantly improved model performance. Hypertension, self-rated health, and smoking were the major health features, while insurance, poverty, and work status were the major demographic features in the predictive model (accuracy=0.97; AUROC=0.88; PPV=0.42).

Conclusion:
Findings underscore the potential utility of ML models in predicting cholesterol screening behaviors after age 50. This could be the basis for developing decision tools for clinicians to identify those with a lower chance of cholesterol screening or make reminders accordingly. The low-cost predictive model might improve the uptake of preventive screening behaviors in middle-aged and older adults.