bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12011: Time in Therapeutic Range and Major Adverse Outcomes in Anticoagulated Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention on Triple Antithrombotic Therapy: The Atrial Fibrillation Undergoing Coronary Artery Stenting (AFCAS) Registry
Authors: Proietti Marco , Airaksinen K.E. Juhani , Rubboli Andrea , Schlitt Axel , Kiviniemi Tuomas , Karjalainen Pasi P , Lip Gregory Y
Published: April 2024

Introduction:
Combination of oral anticoagulation (OAC) and antiplatelet therapy is used in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention stent (PCI-S) implantation but is associated with increased bleeding, especially if triple antithrombotic therapy (TAT) is used.

Hypothesis:
Adverse outcomes in patients prescribed with TAT after a PCI-S are related to quality of anticoagulation control as reflected by time in therapeutic range (TTR).

Methods:
Subgroup analysis from the AFCAS registry in patients assigned to TAT at discharge. TTR was calculated using Rosendaal method. Outcomes were determined for TTR tertiles (T1:<56.8%, T2:56.9-93.8%, T3:>93.9%).

Results:
Of 963 patients originally enrolled, 470 (48.8%) were prescribed TAT at discharge and had all data available for this analysis. Median [IQR] TTR was 80.0% [45.3-100%]. After a mean±SD follow-up of 343±94 days, crude major bleeding rates were progressively lower with increasing TTR tertiles (T1 vs. T2 vs. T3: 10.3% vs. 4.7% vs. 2.3%, p=0.006). Kaplan Meier survival analysis demonstrated a progressively lower risk for major bleeding across TTR tertiles (p=0.006; Figure). Patients in the highest TTR tertile (T3) had a lower risk for major adverse coronary and cerebrovascular events (MACCE) compared to those in T1 and T2 (Log-Rank:4.420, p=0.036). On Cox regression analysis (adjusted for age, gender, AF type, CHA
2
DS
2
-VASc, PCI-S indication/setting), T2 and T3 were inversely associated with major bleeding (HR:0.39, 95%CI:0.15-1.00, p=0.050 and HR:0.21, 95%CI:0.07-0.63, p=0.005). Continuous TTR was also inversely associated with major bleeding (HR:0.98, 95%CI:0.97-0.99, p<0.001). Patients in T3 had the lowest risk of MACCE (HR:0.58, 95%CI:0.35-0.96, p=0.033).

Conclusions:
In AF patients undergoing a PCI-S prescribed TAT, good quality anticoagulation control (as reflected by TTR) is related to better cardiovascular and bleeding outcomes during follow-up.
Abstract 12012: Dysregulated Adenosine Methylation of RNA in Myocardial Ischemia
Authors: Mathiyalagan Prabhu , Martins Adriano , Liang Yaxuan , Chen Jiqiu , Kohlbrenner Erik , Lebeche Djamel , Trivieri Maria G , Ishikawa Kiyotake , Fish Kenneth , Hajjar Roger J , Sahoo Susmita
Published: April 2024

Introduction:
Emerging evidence suggests that post-transcriptional modifications of mRNAs are vital to their stability, nuclear export, cellular compartmentalization, translation to proteins, degradation and stem cell pluripotency. However, such mechanisms remain unexplored in mature post-mitotic tissues such as the mammalian myocardium, especially under its pathophysiological remodeling. Here, we investigated the role of N6-methyladenosine (m6A), the most prevalent chemical modification in RNA, in myocardial ischemia.

Methods and Results:
We studied post-mortem human tissues, murine and swine models of myocardial ischemia and demonstrated for the first time that m6A methylation of mRNA in the ischemic left ventricle (LV) is significantly increased when compared with non-ischemic LV. We found that increase in m6A methylation is conserved in human, pig and mice and have global effect in post-ischemic cardiac remodeling, affecting mRNA, miRNA and protein expressions, and myocyte function. We identified that the expression of m6A demethylase, fat mass and obesity-associated protein (FTO) is decreased in post-ischemic human and mouse myocardium. Using loss-of-function gain-of-function studies in isolated primary adult rat cardiomyocytes, we identified FTO as a direct regulator of m6A methylation, SERCA2a expression and cardiomyocyte function including Ca
2+
transient, decay and sarcomere shortening. Remarkably, in primary cardiomyocytes under hypoxia stress, FTO expression was down regulated resulting in increase in mRNA methylation, decrease in SERCA2a expression and compromised cardiomyocyte function, all of which was restored by adenovirus-mediated overexpression of FTO under hypoxia. Finally, using methylated RNA pull-down assay of RNA from human ischemic and control LV tissues, we have demonstrated that SERCA mRNA is hypermethylated under ischemia and that SERCA demethylation by FTO is essential for SERCA mRNA expression and protein synthesis.

Conclusions:
We have discovered a novel pathomechanism by which FTO, a RNA demethylase, plays a critical role in cardiac homeostasis and cardiomyocyte function under ischemia. Our discovery opens up a new paradigm for our understanding of post-ischemic cardiac remodeling.
Abstract 12037: Metabolite Profiles Associated With Variation in Visceral Adiposity: The Multi-Ethnic Study of Atherosclerosis
Authors: Neeland Ian J , Ayers Colby , Tzoulaki Ioanna , Karaman Ibrahim , Boulange Claire , Vaidya Dhananjay , Punjabi Naresh , Allison Matthew , Herrington David , Greenland Phil
Published: April 2024

Introduction:
Understanding the association between serum metabolites and variation in visceral adipose tissue (VAT) content could provide novel insights into the pathogenesis and prevention of obesity and obesity-associated diseases.

Methods:
We analyzed data from participants in the Multi-Ethnic Study of Atherosclerosis who underwent untargeted metabolomics profiling of blood serum collected between 2000-2002 by proton nuclear magnetic resonance (
1
H NMR) spectroscopy on a Bruker DRX600 spectrometer at 600 MHz using a standard 1-D spectrum and subsequent assessment of VAT area (cm
2
) between 2002-2005 by computed tomography. Multivariable linear regression was used to evaluate the associations between NMR metabolic features and VAT area. Metabolites were identified with spiking and peak connectivity and with spectral library verification. A false discovery rate threshold of 1% was applied for statistical significance.

Results:
1,102 participants were included with median age 63 years; 52% male; 40% white; median BMI 27 kg/m
2
. 30,590 metabolomic spectral features were evaluated. After multivariable adjustment for age, sex, race, data acquisition phase (batch 1 or 2), socioeconomic status score, smoking, physical activity, and body mass index, 2,113 spectral variables representing 14 distinct metabolites were significantly associated with VAT area (
Figure
). After additional adjustment for fasting plasma glucose or diabetes status, all metabolites except glycerol remained statistically significant.

Conclusions:
Using an untargeted metabolomics approach, we found a distinct BMI and glucose independent metabolite profile associated with excess visceral adiposity. These findings provide insight into the pathophysiologic and metabolic mechanisms associated with variation in VAT burden. Further identification of unknown metabolites and external validation are needed.
Abstract 12091: Higher Chadsvasc Scores but Similar Complication and Mortality Rates in Women With Atrial Fibrillation Over 1 Year in an Outpatient Cardiology Setting
Authors: Foltz Tiffany , Singh Narendra , Chandra Sandeep , Song David , Yan Linda , Suh David
Published: April 2024

Background:
Gender differences in atrial fibrillation are recognized with women having a higher stroke risk and therefore having an extra point attributed within the CHADSVasc score. We evaluate if a higher score affects oral anticoagulant use (OAC) and outcomes over 1 year.

Methods:
Retrospective chart review of all pts being treated for atrial fibrillation in a single, multi-site suburban, outpatient cardiology practice for the calendar year 2014.

Results:
Of the 1366 pts being followed 645 (47.2%) were females. Females had a higher CHADSVasc score (4.0± 1.6 vs 2.7± 1.6, p=0.001). This difference was driven by the CHADSVasc components of age > 75 (47% vs 31%, p=0.001) and cerebrovascular accidents (16% vs 12.5%, p=0.05). Other components were similar-heart failure (26 vs 26%), hypertension (82 vs 81%), diabetes (31 vs 31%) vascular disease (12 vs 13%). The % of females vs males having a CHADSVasc score of 1-3 was (32 vs 68%, p<0.00001) 4-6 (66 vs 34%, p<0.00001) and 7-9 (80 vs 20%, p=0.000001). Females had a higher ejection fraction (56 vs 53%, p=0.6) and more valvular heart disease (32 vs 24%, p=0.0002) but similar BMI (29 vs 29). Paroxysmal AF was similar (72% vs 70%) Females were more likely to have Medicare coverage vs private insurance (64% vs 29%, p=0.000054) and more often of black ethnicity (35 vs 23%, p=0.000001). Females were equally likely to be prescribed warfarin vs a NOAC (48 vs 45.1%, p=0.3) and time in therapeutic range was similar at 50%. There was no difference in the number of pts not receiving an OAC (49.7 vs 50.3%, p=0.3) Stroke and bleeding complication rates over 1 year were similar (9.1% vs 8.5%, p=0.6) as was mortality (3.7 vs 3.9%, p=0.8).

Conclusions:
Our findings confirm that women with atrial fibrillation tend to be older which results in a higher CHADSVasc score. This however did not appear to translate into a higher utilization of OAC compared to men but also did not worsen 1 year outcomes. If validated in other datasets then it may be necessary to revisit if females warrant an extra point on the CHADSVasc scale in the contemporary AF population.
Abstract 12189: Gender Differences in Intra-Operative Blood Transfusions: Analysis of 54,122 Coronary Artery Bypass (CABG) Procedures
Authors: Weinstein Samuel , Tesdahl Eric , Stammers Albert , Mongero Linda B , Dickinson Timothy A , Toyoda Yoshiya , Morris Rohinton , Firstenberg Michael , Mosca Lori J
Published: April 2024

Background/Hypothesis:
Women have higher morbidity and mortality associated with CABG procedures than men. The extent intra-operative red blood cell (RBC) transfusions contribute to gender differences in surgical outcomes is not established. We hypothesized that women are at increased risk for RBC transfusions due to lower pre-op hematocrit (Hct) and blood volume, but that other factors may also contribute.

Methods:
Consecutive, non-reoperative CABG procedures from 189 institutions (2012 -2015) were reviewed. Gender differences and odds ratios for intra-operative transfusion were evaluated with logistic regression models adjusting for age, blood volume (Nadler formula-to normalize for height and weight), procedure acuity, net extracorporeal circuit prime volume, use of retrograde autologous priming, first Hct in OR, nadir Hct on cardiopulmonary bypass (CPB), volume added on CPB, ultra-filtration volume, urine output on CPB, and procedure duration.

Results:
Among 54,122 patients (25.3% female), 21.9% (n=11,901) received a RBC transfusion. Compared to men, female patients were older (66 yrs vs. 64 yrs, p<.001), had lower blood volumes (4.3L vs. 5.6L, p<.001), and lower pre-op Hct (32.9% vs. 37.2%, p<.001). Transfusion rates were 3-fold higher in women vs. men (45.1% vs 13.7%, p<.001). Even after adjustment for independent predictors of intra-operative transfusion, women remained at increased risk vs men (OR = 1.3, 95% CI = 1.2 -1.4). No gender differences in transfusion rates were observed for Hct 21%-23% (Figure).

Conclusions:
Women have an increased risk of intra-operative RBC transfusion vs men. After adjusting for height and weight, much of this risk is due to gender differences in pre-op Hct and blood volume, however a residual significant risk remained after adjustment. Perfusion strategies aimed at gender differences may minimize unnecessary transfusions. Future study on the impact of gender on transfusion practice in cardiac surgery is warranted.
Abstract 12203: Fxr1 Regulates Inflammatory mRA Stability and Vascular Disease
Authors: Herman Allison , Kelemen Sheri , Haines Dale , Autieri Michael
Published: April 2024

Introduction:
Vascular smooth muscle cells (VSMC) play a critical role in the etiology and progression of many vascular diseases, and reduction of inflammatory gene expression in VSMC is a rational approach to limit the severity of these diseases. HuR is an mRNA stability protein that recognizes AU-rich elements (ARE) present almost exclusively in the 3’UTR of pro-inflammatory gene mRNA. Proteins and pathways which limit HuR activity in vascular cells may reduce inflammatory mRNA stability, but are currently uncharacterized. Using un-biased LC-MS/MS to identify HuR-interacting proteins under different inflammatory conditions, we identified one protein termed Fragile X-related protein (FXR1), which interacts with HuR in inflammatory, but not basal conditions.

Results and Conclusions:
Using immunohistochemical and molecular biological approaches, preliminary data shows that FXR1 expression is increased in VSMC in plaque from atherosclerotic mouse and human arteries. FXR1 translocates from the nucleus into the cytoplasm and co-localizes with HuR in cytoplasm. FXR1 expression is also increased by TNFα and oxLDL stimulation of cultured human VSMC. Importantly, siRNA knock down of FXR1 in VSMC increases inflammatory mRNA stability, increases abundance of ARE-containing inflammatory proteins, and increases cholesterol uptake. Surprisingly, FXR1 expression is also increased by anti-inflammatory interleukins. Since FXR1 is induced by both pro-inflammatory stimuli as well as IL-19, and yet deletion of FXR1 leads to enhanced expression of pro-inflammatory proteins, our overall hypothesis is that FXR1 expression is a negative, compensatory, counter-regulatory mechanism used by VSMC to respond to and dampen inflammation. Our specific hypothesis is that FXR1 antagonizes HuR function by numerous mechanisms leading to a reduction in stability of pro-inflammatory, ARE-containing mRNA. Currently, very little is understood concerning negative regulation of inflammatory mRNA stability, particularly so in vascular disease. Nothing at all is known about FXR1 expression and function in VSMC and vascular disease. This work may identify FXR1 as part of an anti-inflammatory gene expression program and uncover a novel role for FXR1 in vascular disease.
Abstract 12214: Cardiorespiratory Fitness Lowers the Risk of Stroke in African-American Veterans
Authors: Kokkinos Peter , Faselis Charles , Narayan Puneet , Myers Jonathan , Tsimploulis Apostolos , Balish Marshall , Doumas Michael , Pittaras Andreas , Philiben Liam , Karasik Pamela , Moore Hans
Published: April 2024

Introduction:
Stroke incidence is significantly higher in African-Americans (AA) than in any other racial group. Cardiorespiratory fitness (CRF) is associated with a more favorable cardiovascular health. The CRF-stroke incidence association has not been fully explored in AA patients.

Hypothesis:
We hypothesize that the CRF-stroke incidence association will be inverse and graded.

Methods:
From 1985 to 2014, we identified 13,511 AA (mean age: 58±11) with a normal response to an exercise tolerance test (ETT) and no prior history of stroke. We established five fitness categories based on age-stratified quintiles of peak metabolic equivalents (MET) achieved: Least-Fit (4.2±1.2 METs; n=2,708); Low-Fit (6.0±1.2; n=2,914); Moderate-Fit (7.9±1.0 METs; n=2,816); Fit (8.6±1.4 METs; n=2,903); and High-Fit (11.5±2.3 METs; n=2,170). Multivariable Cox model, adjusted for age, BMI, gender, cardiac risk factors, blood pressure, sleep apnea, alcohol dependence and medications, was used to estimate hazard ratios (HR) and 95% confidence intervals [CI], for incidence of stroke across fitness categories. The Least-fit category was used as the reference group.

Results:
During follow-up (median=11.3 years) 703 individuals (5.2%) developed stroke. The risk for stroke was 7% lower for each 1-MET increase in exercise capacity (HR=0.93, CI: 0.90-0.96; p<0.001). When considering fitness categories, stroke risk was lower by: 27% (HR=0.73; CI: 0.59-0.89) in the Low-Fit individuals; 34% (HR= 0.66; CI: 0.53-0.74) in the Moderate-Fit; 41% lower in the Fit (HR= 0.59; CI: 0.45-0.75) and 43% in High-Fit individuals (HR= 0.57; CI: 0.44-0.74).

Conclusions:
CRF was inversely related to stroke incidence in AA. The risk declined progressively with increasing CRF and was over 40% lower for individuals in the two highest fitness categories.
Abstract 12227: New Insights Into Calcification and Aortic Stenosis Using 4-dimensional Computed Tomography.
Authors: Jenkins William S , Simard Louis , Hourdain Jérome , Clavel Marie-Annick , Enriquez-Sarano Maurice
Published: April 2024

Background:
Aortic Valve Calcification (AVC) is intrinsic to aortic stenosis (AS). While established concepts assume homogeneous calcification causing AS, wide variability in hemodynamic severity at any given AVC burden suggests other operative mechanisms. Multidetector computed tomography (MDCT) now accurately measures global AVC, but AVC spatial distribution remains elusive due to imaging orientation.

Methods and Results:
We developed ‘en-face’ imaging by re-registration of 4D-MDCT to quantify AVC spatial distribution and analyzed global AVC load and AVC distribution in 418 patients with AS (76±9 years; mean gradient 35±17 mmHg). 4D-volume-rendered MDCT datasets were re-oriented to en-face view of aortic valve for AVC spatial scoring with individual cusp calcification load, cusp-edge calcification and AVC asymmetry. Despite high total AVC load (450 [250-666] AU/cm
2
), asymmetry was frequent (50%), with a difference between most- and least-calcified cusp of 112 [66-182] AU/cm
2
. Maximum AVC was in the non-coronary cusp in 61% (p<0.001). Cusp edge calcification was none-mild in 26%, moderate in 62% and severe in 12%. Adjusting for total AVC, severe AS (mean gradient >40 mmHg) was more likely with symmetrical AVC (odds ratio [OR] 2.36, p<0.001) and with edge calcification moderate (OR 4.16, p=0.001 vs none-mild) to severe (OR 10.7, p=0.001). Inclusion of AVC distribution improved models predicting AS severity over total AVC (p<0.001).

Conclusions:
Four-dimensional MDCT en-face re-registration and AVC quantitation provides new insight into AS pathophysiology. Contrary to classical concepts, AVC is frequently inhomogeneous and asymmetric. Hemodynamic AS severity is independently affected not only by global AVC but also by variations in AVC distribution and location within cusps, emphasizing the importance of 4D AVC assessment in AS. Impact of quantified AVC asymmetry and location on outcome of transcutaneous aortic valve replacement should be evaluated.
Abstract 12459: Fibroblast Growth Factor-23 and Incident Heart Failure With Reduced versus Preserved Ejection Fraction in the Multi Ethnic Study of Atherosclerosis
Authors: Almahmoud Mohamed Faher , Soliman Elsayed Z , Bertoni Alain G , Kestenbaum Bryan , Katz Ronit , Lima Joao A , Ouyang Pamela , Miller Paul E , Michos Erin D , Herrington David M
Published: April 2024

Introduction:
Higher FGF-23 levels are associated with incident heart failure (HF) in the Multi-Ethnic Study of Atherosclerosis. FGF-23 is also associated with left ventricular hypertrophy and diffuse myocardial fibrosis in experimental models. Whether FGF-23 association with HF is similar for reduced (HFrEF) and preserved (HFpEF) ejection fraction is not well established.

Hypothesis:
Higher FGF-23 levels are associated with increased risk of HFpEF.

Methods:
We studied 6,549 participants (mean age 62 ± 10 yrs, 53% women, mean eGFR of 81 ± 18 m,/min/1.53m
2
) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of cardiovascular disease at baseline (2000-2002). HF events were ascertained by an adjudication committee for a mean follow-up of 11.1 years. We classified HF events as HFrEF (ejection fraction (EF) <50%) or HFpEF (EF ≥50%) at the time of diagnosis. Cox proportional hazard regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between baseline serum FGF-23 and incident HFrEF and HFpEF. Models were adjusted for age, sex, race/ethnicity, education, study site, smoking, diabetes, systolic blood pressure, use of antihypertensive medications, HDL-C, LDL-C, C-reactive protein, eGFR, and log urine albumin creatinine ratio.

Results:
A total of 227 HF events occurred during follow-up, of which 125 were classified as HFrEF. In the fully adjusted model, associations of FGF-23 with heart failure events tended to be stronger for HFpEF than for HFrEF (HR 2.1 vs. 1.5 per doubling of FGF-23; Table). However, these associations were not statistically distinguishable.

Conclusion:
FGF-23 association with HF is stronger for HFpEF than HFrEF in a population-based cohort. The qualitative difference in strength of associations of FGF-23 with HFpEF and HFrEF is consistent with experimental data demonstrating effects of recombinant FGF-23 on cardiac hypertrophic pathways.
Abstract 12477: Association of Age and Outcome After Bidirectional Cavopulmonary Anastomosis
Authors: Koth Andrew M , Algaze Claudia A , Hao Shiying , Shin Andrew Y
Published: April 2024

Introduction:
The Glenn procedure has traditionally been performed between 4-6 months of age. Several studies have investigated the benefits of performing the procedure earlier, to shorten the inter-stage period. No studies have specifically looked the unintended consequences of early Glenn procedures (< 4 months) related to post-operative outcomes.

Hypothesis:
We hypothesized that after the Glenn procedure, younger patients would have a longer post-operative length of stay.

Methods:
All patients undergoing the Glenn procedure between 1/2010 and 7/2015 were included in this retrospective cohort study. Demographic data, including baseline saturations, medications, length of intubation and chest tube drainage were recorded. Mean post-operative length of stay was calculated. Standard descriptive statistics were used. A univariable analysis was conducted using the appropriate test based on data distribution. A multivariable analysis was then completed using predictors from the univariable analysis.

Results:
Over the study period, 50 patients were included. Patients were separated into two cohorts[≥4 months (28) and <4 months (22)]. Other than height and weight, the two cohorts were indistinguishable in their pre-operative saturation, medications, catheterization hemodynamics, atrioventricular valve regurgitation and ventricular function. Length of intubation and chest tube drainage were not different between the cohorts. Younger age was associated with longer post-operative length of stay [mean 14.6 (±15) vs. 7.7(±5.1) days,
p
=0.03]. In a multivariable regression analysis, in addition to ventricular dysfunction (
B
coefficient 8.8,
p
=0.05), Glenn procedures performed before 4 months were independently associated with longer length of stay (
B
coefficient -6.9,
p
=0.03).

Conclusion:
We found that elective Glenn procedures performed after 4 months of age had improved outcomes compared to a younger cohort. These findings suggest that balancing timing of surgery to decrease the inter-stage period should take into consideration differences in post-operative recovery with early operations.
Abstract 12482: Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Based on History of Cardiovascular Disease or Cardiovascular Risk Factors
Authors: Davies Michael J , Merton Katherine , Vijapurkar Ujjwala , Yee Jacqueline , Qiu Rong
Published: April 2024

Introduction:
Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and use of concomitant medications. Canagliflozin (CANA), an SGLT2 inhibitor, has been shown to improve glycemic control, body weight, and blood pressure (BP) with a favorable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of CANA in patients with T2DM based on CV disease history/risk factors.

Methods:
These analyses were based on pooled data from four 26-week, placebo (PBO)-controlled, Phase 3 studies that evaluated CANA 100 and 300 mg in patients with T2DM (N = 2313; mean A1C, 8.0%; body weight, 89 kg; systolic BP [SBP], 128 mmHg). Changes from baseline in A1C, body weight, and SBP at Week 26 were assessed in subgroups of patients based on history of CV disease (Y/N), history of hypertension (Y/N), baseline statin use (Y/N), and number of CV risk factors (0/1 vs ≥2). Safety was based on adverse event (AE) reports.

Results:
CANA 100 and 300 mg lowered A1C, body weight, and SBP versus PBO in patients with or without CV disease history/risk factors (
Table
). At Week 26, A1C reductions with CANA 100 and 300 mg relative to PBO were generally similar in patients with history of CV disease (–0.95% and –1.07%) versus no CV disease (–0.71% and –0.90%), history of hypertension (–0.72% and –0.89%) versus no hypertension (–0.73% and –0.95%), baseline statin use (–0.77% and –0.99%) versus no statin use (–0.69% and –0.85%), and ≥2 CV risk factors (–0.74% and –1.02%) versus 0/1 CV risk factor (–0.72% and –0.87%). Similar body weight and SBP reductions were also seen with CANA versus PBO across subgroups. Incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups.

Conclusions:
CANA was efficacious and generally well tolerated in patients with T2DM regardless of CV disease history/risk factors.
Abstract 12489: Association of Longitudinal Blood Pressure Changes and Kidney Function Decline: Findings From the Multi-Ethnic Study of Atherosclerosis
Authors: Judson Gregory L , Rubinsky Anna D , Scherzer Rebecca , Shlipak Michael , Katz Ronit , Kramer Holly , Ix Joacim , Jacobs David , Odden Michelle , Peralta Carmen A
Published: April 2024

Background:
Few studies have examined the association of blood pressure (BP) change over time with kidney function decline. We hypothesized that increasing systolic blood pressure (SBP), decreasing diastolic blood pressure (DBP), and widening pulse pressure (PP) trajectory would be associated with worsening renal function, independent of baseline BP, among persons with relatively preserved estimated glomerular filtration rate (eGFR) and free from cardiovascular disease at baseline.

Methods:
We used data from 4,156 participants in the MESA Study who had at least two BP measurements from study year 0 to year 5 and eGFR measurements at year 5 and 10. Participants were then grouped into one of three groups based on the distribution of change (top 20% = increasers, middle 21-79% = stable, bottom 20% = decreasers). We calculated eGFR from cystatin C and defined rapid decline as a >30% decrease in eGFR. We used multivariable logistic regression adjusting for demographics, baseline eGFR and BP to determine associations of BP change category with later renal function decline. We also estimated the association of change in BP with annual change in eGFR using adjusted linear regression.

Results:
The stable SBP group had a mean age of 59, was 50% male, 41% white, and had 29% of participants on an anti-hypertensive medication. The increasing SBP group was similar except for having fewer men (43%). Median year 0 and year 5 SBP for increasing SBP was 110 and 131, for stable 119 and 118, for decreasing 145 and 119 mmHg respectively. Increasing SBP and widening PP trajectory were associated with higher odds of rapid renal function decline compared to stable groups after adjusting for all covariates including baseline BP. Decreasing SBP was not associated with rapid renal function decline after adjusting for baseline BP. Similar findings were seen with annual renal function decline.

Implication:
Increasing SBP and widening PP appears to increase the risk for accelerated kidney function decline.
Abstract 12521: Intracellular Fatty Acid Balance Regulated by Elovl6 Plays a Notable Phenotypic Response of Vascular Smooth Muscle Cells via AMPK-KLF4-Dependent Signaling
Authors: Matsui Hiroki , Sunaga Hiroaki , Iso Tasuya , Koitabashi Norimichi , Matsuzaka Takashi , Shimano Hitoshi , Yokoyama Tomoyuki , Kurabayashi Masahiko
Published: April 2024

Introduction:
Krüppel-like factor 4 (KLF4) is a transcription factor controlling differentiation and proliferation of vascular smooth muscle cells (VSMC). We recently showed that disruption of elongation of long chain fatty acids 6 (Elovl6), rate-limiting enzyme catalyzing the elongation of saturated and monounsaturated, suppressed VSMC proliferation and differentiation via AMP-activated protein kinase (AMPK) activation. However, little is known about the role of KLF4 in passing metabolic stress on to the regulating VSMC proliferation and differentiation.

Hypothesis:
We examine whether KLF4 is involved in the suppression of Elovl6-disrupted VSMC proliferation.

Methods and Results:
Immunohistochemical staining of aorta revealed that KLF4 expression was markedly increased in Elovl6-null (Elovl6
-/-
) mice compared with wild-type mice. Western blot analysis also showed that the KLF4 expression was markedly induced in human aortic smooth muscle cell (HASMC) with siRNA-mediated Elovl6 depletion and in Elovl6
-/-
mouse aorta. Previous study demonstrated that Elovl6 depletion in VSMC altered long chain fatty acid (LCFA) composition in which palmitate was increased and oleate was decreased. Accordingly, palmitate increased and oleate decreased KLF4 expression. To clarify the effects of KLF4 on cell-cycle regulatory gene expressions and cell proliferation, we examined a siRNA-mediated knockdown of KLF4 in HASMC. The expression of SMα-actin and SM22α genes were decreased in siKLF4-introduced HASMC, and siElovl6-triggered inhibition of cell proliferation was partially recovered by concomitant treatment of siKLF4. Elovl6 depletion in HASMC markedly induced p53 phosphorylation and p21 expression, whereas depletion of KLF4 abrogated the induction of these proteins. We further identified the treatment with AMPK activator (AICAR) significantly induced KLF4 expression, whereas AMPK inhibitor (compound C) markedly inhibited the AICAR-induced or Elovl6-knockdown-induced KLF4 expression.

Conclusions:
Overall, our results indicate that KLF4 is activated by metabolic stress triggered by perturbed intracellular LCFA composition and AMPK-KLF4 axis plays an indispensable role in controlling VSMC proliferation and differentiation
Abstract 12540: Epigenetic Modulation of Macrophage Polarization Toward a Proinflammatory Phenotype Increases the Susceptibility to Insulin Resistance in Adult Offspring of High-fat Diet Fed-dams
Authors: Wada Naotoshi , Yamada Hiroyuki , Motoyama Shinichiro , Terada Kensuke , Yamamoto Keita , Saburi Makoto , Kikai Masakazu , Wakana Noriyuki , Matoba Satoaki
Published: April 2024

Background:
Maternal high-fat diet (HFD) has been shown to promote the development of metabolic disorders such as obesity and insulin resistance in adult offspring; however, its underlying mechanisms remains undefined.

Method and Result:
Eight-week-old female wild-type mice were fed a HFD or normal diet (ND) one week prior to mating, and received either HFD or ND during gestation and lactation. Offspring of both groups were fed a ND after weaning and then fed a HFD from 8 to 20 weeks of age. After 4 weeks of HFD feeding, insulin tolerance test in male offspring of HFD-fed dams (O-HFD) showed a significantly impaired insulin sensitivity compared with those of ND-fed dams (O-ND), which was more prominent after 8 weeks of HFD feeding. In contrast, glucose tolerance did not differ between the 2 groups after 4 and 8 weeks of HFD feeding. The weight of epididymal white pads and adipocyte size were comparable between the 2 groups. Although the fraction of macrophages (F4/80
+
CD11b
+
) in epididymal white pads assessed by flow cytometry did not differ between the 2 groups, the ratio of M1/M2 macrophages (M1:CD11c
+
CD206
-
, M2:CD11c
-
CD206
+
) was markedly increased in O-HFD compared with O-ND (18.3 vs. 1.6, O-HFD vs. O-ND;
P
< 0.05). We examined the effect of maternal HFD on the bone marrow (BM) monocytosis and macrophage polarization in adult offspring before HFD feeding. The fraction of BM pro-monocyte (CD11b
high
Ly-6G
low
) did not differ between the 2 groups; however, BM-derived macrophages (BMDMs) in O-HFD showed a higher expression levels of M1 marker genes after stimulation of IFN-γ, concomitant with the lower expression levels of M2 marker genes after stimulation of IL-4. Further, BMDMs in O-HFD showed a 2.9-fold increase in the mRNA expression levels of histone deacetylase 3 (
HDAC3
) after stimulation of IL-4 (
P
< 0.05), whereas its expression was decreased by 64 % in O-ND (
P
< 0.05).

Conclusion:
Our findings demonstrated for the first time that BMDMs in adult offspring of HFD-fed dams are likely to be polarized toward a proinflammatory phenotype, thereby contributing to the increased susceptibility to insulin resistance. Modulation of epigenetic-mediated macrophage polarization could be a potential therapeutic target for preventing metabolic disorders.
Abstract 12565: Transitional Care Model Decreases Readmission in the Left Ventricular Assist Device Patients
Authors: Iseler Jackeline
Published: April 2024

Decreasing 30-day readmission rates is critical to minimizing penalties from Medicare and Medicaid. Hospital readmission rates in the Left Ventricular Assist Device (LVAD) programs are 26% to 76% and are highly contingent on successful transitions to home. A Transitional Care Model (TCM) approach is comprehensive, holistic and involves collaboration between the patient and their caregiver. The efforts guided by the TCM, in managing symptoms, education of self-management, coordinating care, and maintaining relationships, are patient and caregiver focused. The principles of the TCM involve patient screening to evaluate for their risk for readmission. The purpose of this pilot study is to evaluate the effectiveness of an intervention based on the TCM in reducing readmission rate. This pilot of the TCM was conducted at a single major medical center which places approximately 60 LVADs yearly. A total of ten participants were enrolled using convenience sampling between June and August of 2015. The eight-week program consisted of an individualized self-management care plan and a combination of weekly follow-up home visits or phone calls. Medical records were reviewed in addition to obtaining participant satisfaction surveys. Pilot evaluation is based on the 30-day readmission rate, participant satisfaction, and program costs. Of the ten participants, six completed the program. The 30-day readmission rate for the six was 16.7%, as compared to the hospital’s readmission rate of non-enrolled participants at 32.1%. The participants expressed overall satisfaction with the program and would willingly use the program if needed; they also said they would recommend the program to family and friends. The total program costs were estimated at $125,444. The cost of readmission at the 32.1% rate and 16.7% are $674,100 and $350,700 respectfully; with a potential cost avoidance of the TCM program of $248,356. Patients with an LVAD experience compounding stressors of managing a chronic illness, an acute surgical intervention, and a life-sustaining device. The TCM pilot was able to achieve successful outcomes in the midst of these stressors. Further inquiry in interventions consistent with TCM is needed to advance care and transitions in the LVAD patient population.
Abstract 12571: Social Network Analysis Demonstrating Impact of Resuscitation Outcome Consortium (ROC) on Collaboration
Authors: Sequeira Denisse , Patterson Daniel , Guyette Francis X
Published: April 2024

Introduction:
National Institute of Health (NIH) funded ROC to create an infrastructure that would support clinical resuscitation research and facilitate collaboration among investigators from numerous institutions. While collaborations are key elements of scientific productivity, few have formally quantified collaboration over time. Social Network Analysis (SNA ) is widely used in social and clinical science to quantify and illustrate network relationships.We sought to characterize collaboration and cohesion amongst ROC investigators using (SNA) techniques.

Hypothesis:
The number of collaborations between participating sites increased after the introduction of a clinical research consortium.

Methods:
Lists of publications were abstracted from PubMed for investigators listed as contributing authors on at least one ROC publication. Publications were abstracted from two different time periods: 2003-2005 and 2013-2015 the time periods before the creation of ROC and after. The number of co-authorships was used to construct a matrix analyzed using UCINET Version 6.205 to calculate density as well as a network sociogram illustrating the collaborations. Density refers to the overall measure of interaction. Values range from 0-100, higher values indicate greater cohesion and collaboration between nodes (members) in a defined network.

Results:
The network density was 1.4% in the time period before ROC and increased to 29.7%. In the pre-ROC period, there were 56 investigators within the 10 participating sites which grew to 126 investigators by 2015. In the pre-ROC epoch of time (3 years) there were 418 total publications which increased to 1,558 by the 2013-2015 epoch.

Conclusions:
ROC helped facilitate collaboration resulting in an increase in both co-authored publications and network density that might not have existed without ROC. It also created a framework for interaction amongst investigators with shared clinical interests across multiple institutions.
Abstract 12592: Targeted Delivery of AntimiR-23a Using Ultrasound and Microbubbles Suppresses Cardiac Hypertrophy and Improves Cardiac Function in vivo
Authors: Kopechek Jonathan A , McTiernan Charles F , Chen Xucai , Feroze Rafey , Qin Bin , Cyriac Jissy , Lavery Linda , Whitehurst Daniel , Villanueva Flordeliza S
Published: April 2024

Background:
MicroRNAs (
miRs
) are dysregulated in various cardiovascular diseases. An antimiR against miR-23a suppressed hypertension-induced cardiac hypertrophy in preclinical models, but clinical translation is limited by a lack of cardiac-targeted delivery systems. Ultrasound-targeted microbubble
(MB)
destruction
(UTMD)
is a novel therapeutic delivery platform that utilizes MBs as nucleic acid carriers and offers a non-invasive image-guided approach to target delivery of molecular therapeutics to the heart. We hypothesized that cardiac delivery of an antimiR against miR-23a using UTMD suppresses cardiac hypertrophy and improves cardiac function in hypertensive mice.

Methods:
Cationic lipid MBs were loaded with negative control antimiR (
NC
) or antimiR-23a. C57BL/6 mice were implanted with phenylephrine-loaded osmotic minipumps (100 mg/kg/d) and received UTMD treatments (1.3 MHz, MI setting=1.0) with 300 pmol antimiR 0, 3, and 7 days later. A third group (no phenylephrine, No-PE) of age matched mice received no treatments. At 2 weeks, miR-23a levels were measured using RT-PCR. Left ventricular
(LV)
mass and function were serially assessed with echocardiography.

Results:
UTMD treatment with antimiR-23a knocked down cardiac miR-23a by 41 ± 8% compared to UTMD treatment with NC (n=8-9/group, p<0.01). As expected, phenylephrine increased LV mass relative to No-PE mice. However, compared to treatment with UTMD + NC, LV mass in mice with UTMD + antimiR-23a was 16 ± 2% lower after 1 week (p < 0.05), and remained lower during the study (p=0.06) (Figure 1). By 2 weeks, fractional shortening had decreased in UTMD + NC but was preserved in UTMD + antimiR-23a (45.2% vs. 37.7%, p < 0.05).

Conclusions:
To our knowledge, this is the first study to demonstrate suppression of cardiac hypertrophy and preservation of cardiac function with UTMD-targeted delivery of a miRNA inhibitor. Our data suggest that UTMD could be used to deliver other miRNA therapeutics for cardiac therapy.
Abstract 12654: PBI-4050 Therapy Selectively Improves Pulmonary Hypertension, Lung Remodeling and Right Ventricular Function in Heart Failure With Reduced Ejection Fraction
Authors: Nguyen Quang T , Sirois Martin , Calderone Angelo , Tardif Jean-Claude , Shi Yanfen , Gagnon Lyne , Dupuis Jocelyn
Published: April 2024

Introduction:
There is currently no approved treatment for the most prevalent form of PH that is associated with left heart disease (Group II PH). Heart failure with reduced ejection fraction (HFrEF) causes lung remodeling characterized by myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome contributing to PH and RV dysfunction.

Hypothesis:
We evaluated PBI-4050, a novel first-in-class agent with anti-fibrotic and anti-proliferative actions, for the treatment of PH in a model of HFrEF.

Methods:
HFrEF was induced by myocardial infarction (MI) after coronary artery ligation in rats. Two weeks after surgery, sham-operated and MI groups were treated with PBI-4050 (200 mg/kg/day by gavage) or with saline for 3 weeks. Animals were analyzed according to pathological infarct size into large MI (≥35% LV) and small to medium MI (< 35%). Hemodynamic evaluation was performed with microtip cathethers and lung function testing evaluated with a Flexivent respirator. Cardiac ultrasound was performed at 2 weeks and at 5 weeks. Scar size and lung fibrosis were quantified by histology.

Results:
Pathological infarct size correlated with echocardiographic wall motion score index (r
2
=0.73, p<0.001). Large MI (≥35% LV) resulted in PH and RVH with a restrictive lung syndrome. For a similar infarct size, PBI-4050 did not affect LV function but markedly reduced PH and RVH. The compensatory increase in RV contractility was normalized by PBI-4050. PBI-4050 reduced lung remodeling evidenced by a reduction in lung weight and improved respiratory compliance. Finally, lung fibrosis was reduced by PBI-4050 with histological evidence of reduced alveolar wall cellular proliferation.

Conclusions:
PBI-4050 effectively reduces PH and RVH in HFrEF by reducing lung fibrosis and remodeling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function without affecting LV function. PBI-4050 is a promising therapy for group II PH.
Abstract 12739: Gap Junction Protein Beta 4 Plays an Important Role In Cardiac Hypertrophy and Cardiac Function in Human and Zebrafish
Authors: Okamoto Ryuji , Goto Itaru , Nishimura Yuhei , Kobayashi Issei , Hashizume Ryotaro , Dohi Kaoru , Yamada Norikazu , Tanaka Toshio , Ito Masaaki
Published: April 2024

Introduction:
Gap junction protein beta 4 (GJB4) encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. Mutations in this gene remain unknown to be associated with hypertrophic cardiomyopathy (HCM) and cardiac dysfunction.

Hypothesis:
Our hypothesis is that mutations in GJB4 can cause familial HCM, which can progresses into dilated-phase HCM (d-HCM).

Methods:
We have previously examined a patient and her elder brother who both presented with complicated severe HCM and whose parents are married cousins. The elder brother had died suddenly as a child and the autopsy demonstrated the development of HCM. The patient was diagnosed with HCM, which progressed to d-HCM during the 20-year follow-up. The patient has recently undergone cardiac transplantation. The parents are healthy. We hypothesized that an autosomal recessive mutation caused their familial HCM. The whole-exome sequencing was performed from each of the three participants. We generated knockout zebrafish of GJB4 and ELP2 by CRISPER/Cas9 system and analysis the volume and function of ventricle at five days post fertilization (dpf).

Results:
The gene exome analysis showed 34 single nucleotide polymorphisms (SNPs) that caused amino acid change for which the patient was homozygous and both parents were heterozygous after excluding all known common (>10%) SNP gene mutations in the dbSNP. Among them,
GJB4
and
ELP2
were the identified genes that are possibly associated with cardiac muscle. The PolyPhen-2 scores of mutations in
GJB4
and
ELP2
were 1.000 and 0.001 respectively. The identified missense mutation was a 981 A>C nucleotide transition in GJB4. The resultant E204A substitution replaces a polar carboxylic glutamate with a nonpolar alanine. The endodiastolic volume was significantly lower in GJB4-KO (94pl, p<0.01) and ELP2-KO (95pl, p<0.01) than in wild type (WT, 145pl) zebrafish at 5 dpf. Furthermore the ventricular ejection fraction was decreased in GJB4 KO (0.66, p<0.01) and unchanged in ELP2-KO (0.80) respectively compared with WT zebrafish (0.82).

Conclusions:
These results indicate both that mutations in
GJB4
and
ELP2
can cause a familial form of HCM and that GJB4 especially may be a new target for treatment of cardiac function and hypertrophy.
Abstract 12743: Risk of Cardiovascular Readmission Within 3 Years Following a Hypertensive Complication of Pregnancy
Authors: Jarvie Jennifer L , Kao David P
Published: April 2024

Introduction:
Women with pregnancies complicated by pregnancy-induced hypertension (PIH) have increased cardiovascular (CV) risk decades later. We sought to determine if these women demonstrate greater CV risk more immediately.

Methods:
Using administrative data, we extracted all hospital-based deliveries in the state of Florida from 2004 through 2013. Deliveries and clinical diagnoses were determined using ICD-9 CM codes. Readmissions to any Florida hospital were identified using unique patient identifiers. Our primary predictor was PIH, defined as a composite of gestational hypertension, pre-eclampsia, and eclampsia. Outcomes of interest were CV readmission, defined as a composite of myocardial infarction, stroke, or heart failure; non-CV readmission, and no readmission within 3 years of index delivery. Clinical profiles and maternal outcomes were stratified by readmission status. The association between risk of readmission and PIH was determined using logistic regression.

Results:
A total of 1,834,166 records from delivering mothers were included (mean age 27.3 ± 6.2 years; 53% white, 25% African American [AA], 20% Hispanic). There were 4,732 CV readmissions and 321,713 non-CV readmissions within 3 years of index delivery. When stratified by readmission status, there was a higher make-up of women with PIH in the CV readmission group compared with the other groups (16.5% CV readmission, 9.3% non-CV readmission, 7.4% no readmission; p<0.001) and a higher rate of obesity (13% CV readmission, 5% non-CV readmission, 3% no readmission; p<0.001). Sixty percent of women in the CV readmission group were AA. Women with PIH had a higher multivariate risk of both CV readmission (OR 1.71; 95% CI 1.48 - 1.86) and non-CV readmission (OR 1.08; 95% CI 1.07 - 1.10). Compared with white women, AA women had the highest risk for CV readmission (OR 3.39; 95% CI 3.17 - 3.63) and Hispanic women had the lowest risk of CV readmission (OR 0.60; 95% CI 0.53 - 0.67) after adjustment for PIH.

Conclusion:
In this diverse sample, women with PIH have a higher risk of CV readmission within 3 years of delivery. Significant racial and ethnic differences were seen in the risk for CV readmission among women with pregnancies complicated by PIH with a markedly higher risk in AA women.