bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12983: mtDNA Damage in Concert With PCSK9 Expression Induces Apoptosis in Vascular Smooth Muscle Cells
Authors: Ding Zufeng , Liu Shijie , Mehta Jawahar L
Published: April 2024

Introduction:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in inducing hypercholesterolemia and associated cardiovascular diseases. Autophagy is considered a protective and adaptive mechanism to promote cell survival, while apoptosis represents cell death program designed to remove injured cells. Exposure of vascular smooth muscle cells (SMCs) to noxious stimuli such as LPS or ox-LDL induces PCSK9 expression and apoptosis.

Methods and Results:
Treatment of human primary vascular SMCs to 20 ng/ml LPS significantly induced both mtDNA damage and PCSK9 expression. mtDNA damage induction with the autophagy inhibitor 3-methyladenine enhanced PCSK9 expression, whereas mtDNA damage inhibition with the autophagy inducer rapamycin reduced PCSK9 expression, indicating an interplay between autophagy, mtDNA damage and PCSK9. Inhibition of DNase II (siRNA) for reduced the extent of mtDNA damage and PCSK9 expression confirmed the role of mtDNA damage in PCSK9 expression. Next, we investigated the role of PCSK9 in the development of apoptosis. We observed that PCSK9 upregulation by hPCSK9 treatment induced and PCSK9 inhibition by siRNA transfection reduced apoptosis of SMCs (measured as TUNEL staining and expression of Bax, Bcl2 and cleaved caspase-3).

Conclusions:
These observations provide a compelling evidence for the role of mtDNA damage in PCSK9 release. Both collectively induce SMC apoptosis during inflammatory states characteristic of cardiovascular diseases, such as atherosclerosis.
Abstract 13041: Worsening Renal Function in Early Phase of Hospitalization Indicates Poor Prognosis of Patients With Acute Heart Failure
Authors: Kawase Yuichi , Hata Reo , Iwasaki Keiichiro , Tada Takeshi , Maruo Takeshi , Katoh Harumi , Kadota Kazushige
Published: April 2024

Background:
Worsening renal function (WRF, serum creatinine rise ≥0.3 mg/dl from admission) has been consistently shown to be among the important prognostic variables in patients admitted for acute heart failure (AHF). However, the relation between the timing of WRF and prongnosis remains unclear.

Methods:
We investigated 464 consecutive patients admitted for AHF between February 2015 and October 2015. After having eliminated patients with acute coronary syndrome and end stage renal disease, we enrolled 377 patients in this study sample (mean age 79.1±12.4 years). The median follow-up period was 225 (interquartile range, 88-330) days. WRF was dichotomized into early or late WRF by using the median of the occurrence day (day 3). The primary end points were all-cause death and a composite of all-cause death or rehospitalization for HF.

Results:
WRF occurred in 42% (n=160: early, 56%; late, 44%). The figure shows the Kaplan-Meier curves of death and death/rehospitalization for heart failure. By multivariate analysis, early phase WRF was an independent predictor of poor prognosis (see Table).

Conclusion:
Only early phase WRF is associated with poor prognosis. Therefore, its prevention remains an important target for treatment of AHF.
Abstract 13042: EP4 Signaling in Smooth Muscle Cells Attracts Inflammatory Immune Responses in the Aorta
Authors: Ishiwata Ryo , Yokoyama Utako , Ichikawa Yasuhiro , Kurotaki Daisuke , Yasuda Shota , Goda Motohiko , Suzuki Shinichi , Masuda Munetaka , Tamura Tomohiko , Ishikawa Yoshihiro
Published: April 2024

Chronic inflammation driven by prostaglandin E
2
(PGE
2
) is a basis for vascular diseases such as abdominal aortic aneurysm (AAA). We have reported that PGE
2
receptor, EP4, is responsible for AAA progression. However, precise molecular mechanisms are unknown. Since EP4 expression was upregulated in smooth muscle cells (SMCs) in human AAA, we hypothesized that EP4 in SMCs promotes vascular inflammatory responses in AAA.

Methods and Results:
EP4 transgenic mice (EP4-Tg) in which EP4 is overexpressed selectively in SMCs under SM22α promoter were generated using Cre-loxP system. Neither EP4-Tg nor littermate non-transgenic mice (Non-Tg) exhibited hypertension, hyperlipidemia, or vascular anomaly at basal condition (male, 12-16 weeks-old). Angiotensin II (AngII) infusion (1.0μg/kg/min) caused AAA rupture-related death in all the EP4-Tg around day14 of infusion, while no AAA were observed in Non-Tg until day28 (
n
=6-7,
P
<0.001). To elucidate initial events leading to AAA, the aortae were analyzed at day4 of AngII infusion, at which no AAA was observed. In EP4-Tg aortae, MMP-9 activity was induced (
n
=6-7,
P
<0.05) and IL-6 production was upregulated (5.0±1.8-fold vs. Non-Tg,
n
=6-7,
P
<0.05). FACS analysis showed that infiltration of Ly6C
hi
inflammatory monocytes was enhanced in EP4-Tg aortae, coinciding with the emergence of MMP-9 expression in resident macrophages but not in Non-Tg counterpart (n=4,
P
<0.01). IL-6 expression was detected primarily in SMC layer in EP4-Tg by immunohistochemistry. Administration of IL-6R antibody (MR16-1, 10mg/kg/2days)
in vivo
inhibited AngII-induced infiltration of Ly6C
hi
monocytes (0.3±0.1-fold,
n
=4,
P
<0.05) and AAA rupture in EP4-Tg (
n
=6,
P
=0.06). Administration of EP4 antagonist (ONO AE3-208, 0.1mg/kg, BID) also inhibited AngII-induced AAA in EP4-Tg (
n
=8,
P
=0.05).
In vitro
, EP4 stimulation induced more abundant IL-6 production in EP4-Tg aortic SMCs than Non-Tg SMCs (33.0±4.8-fold,
n
=4,
P
<0.001), which was attenuated by PKA inhibitor or TAK1 inhibitor. Immunohistochemistry showed abundant expressions of IL-6 and phosphorylated TAK1 in EP4-positive human AAA but not in non-aneurysmal aorta.

Conclusion:
PGE
2
-EP4 signaling in SMCs initiates inflammatory reaction and AAA formation via upregulation of IL-6.
Abstract 13065: Comparison of the Cardiovascular Health Status of the American and French Populations Using Connected Devices
Authors: Brouard Benoît , Vegreville Matthieu , Chieh Angela , Schmidt Nicolas , Sirieix Marie-emmanuelle , Simon Alain
Published: April 2024

Introduction:
Cardiovascular disease is one of the leading causes of mortality in both the United States (US) and France (FR). However, while it causes 1 out of every 3 deaths in the US, the rate is just 1 out of every 5 deaths in FR. The aim of this study was to use connected devices and metrics from the Behavioral Risk Factor Surveillance System (BRFSS) from the American Heart Association to determine the difference in cardiovascular risk factors between the two countries.

Methods:
A questionnaire based on the BRFSS was sent through the Withings Health Mate mobile application to a cohort of 7932 users of Withings devices living in the US and FR. Each user had at least 1 value of weight in the last month and 3 days of steps per day of the week in the last 6 months. For each of the 7 metrics in the BRFSS, we assigned users an optimal, intermediate, or poor status. Body Mass Index (BMI) and Physical Activity (PA) levels were automatically populated using data from Withings devices and database.

Results:
Of the total users, 4342 were from the US, and 3590 were from FR. The study cohort is characterized by a mean age of 43.6 ± 26.7 years old and is composed of 68% of men and 32% of women. The mean scores were 9.5 (US) and 10.0 (FR) (
p<10

-5

). The percentage of each population with an overall optimal score was 56% (US) and 64% (FR) (
p<10

-5

). Differences between the US & FR in the prevalence of poor & optimal status of each risk factor are disclosed below.

Poor status of BMI, PA, hypertension, hyperglycemia and hypercholesterolemia are significantly higher in the US. However, poor status of smoking is significantly higher in FR.

Conclusion:
This study suggests that except for smoking, which is 3 times less frequent in the US than in FR, all other risk factors have more frequent poor status in the US. Such data gives new insights into goals to set to improve cardiovascular health in the US and FR.
Abstract 13071: Impact of Arterial Stiffening on Cardiovascular Markers and Incidence of Cardiovascular Event in Normotensive Patients Without History of Cardiovascular Disease
Authors: Ichikawa Keishi , Sakuragi Satoru
Published: April 2024

Introduction:
Arterial stiffness has been proposed as an important predictor of cardiovascular (CV) event in various groups, such as end-stage kidney disease and hypertensive patients. Although, blood pressure (BP) is one of the most important determinants of arterial stiffening, there are some cases who have a discrepancy between BP and arterial stiffness. In this study, we evaluated the impact of arterial stiffening on impairment of cardiac parameters and incidence of CV event in patients with normal blood pressure.

Methods:
A total of 320 outpatients with normal BP defined as systolic BP less than 140mmHg were enrolled. At baseline, all subjects underwent echocardiography and MDCT. Coronary artery calcification (CAC) was evaluated with Agatston method and CAC score (CACs) was calculated. Arterial stiffness was also assessed with pulse wave velocity (PWV) between brachial and ankle. The subjects were divided into two groups according to the PWV: high PWV group (PWV≥18m/sec, n=89) and low PWV group (PWV<18m/sec, n=231). Cardiac parameters as well as incidence of CV events during the follow-up period were compared between the two groups.

Results:
In linear regression analysis, PWV was significantly associated with CACs and NT-proBNP after adjustment for confounding factors. In multivariate logistic regression analysis, PWV over 18m/sec was significantly associated with CACs over 400 with a hazard ratio of 2.466 (95%CI: 1.012-6.009, p=0.047). Kaplan-Meier analysis showed that high PWV group had higher rate of CV event during the follow-up period of 575 days (20% vs 6%, p=0.0003). In multivariate Cox regression analysis, PWV over 18m/sec was an independent predictor for future CV events with an odds ratio of 2.534 (95%CI: 1.045-6.146, p=0.040).

Conclusions:
Arterial stiffening assessed by PWV is a strong determinants of impairment of cardiac parameters as well as future CV event even in normotensive patients.
Abstract 13090: Increased U Vector Magnitude is Associated With Increased Risk of Sudden Cardiac Death - The Atherosclerosis Risk in Communities Study
Authors: Waks Jonathan W , Kabir Muammar , Sedaghat Golriz , Thomas Jason , Biering-Sørensen Tor , Sotoodehnia Nona , Sitlani Colleen M , Biggs Mary L , Henrikson Charles A , Soliman Elsayed Z , Solomon, Scott D , Post Wendy S , Siscovick David S , Buxton Alfred E , Josephson Mark E , Tereshchenko Larisa G
Published: April 2024

Introduction:
The U wave is a poorly understood electrocardiographic (ECG) manifestation of late ventricular repolarization. The association between U waves and sudden cardiac death (SCD) in the general population is unclear.

Hypothesis:
Large U vector magnitude is associated with increased SCD risk.

Methods:
Data from the Atherosclerosis Risk in Communities study (n=13,705; mean age 54.1±5.8 y; 73% male; 55% white; median follow-up 14 y) were analyzed. U wave onset and offset were identified using a semi-automated approach on XYZ transformed ECG leads. The 3-dimensional U wave loop was reconstructed and smoothed to reduce noise. U loop origin was defined as the point halfway between U-onset and U-offset in 3-dimensional space. Maximum U vector magnitude (UVMmax) was measured as the 3-dimensional distance between U loop origin and the point on the smoothed U loop farthest from the origin (Figure A). Participants with UVMmax >100 μV were excluded due to difficulty differentiating the T wave and U wave on these ECGs. Adjusted Cox proportional hazards models were used to investigate the association between UVMmax and adjudicated SCD.

Results:
Median UVMmax was 9.4 μV. After adjustment for multiple demographic and clinical characteristics, electrolytes, and ECG parameters associated with SCD, UVMmax remained associated with SCD. Each 1 standard deviation increase in UVMmax was associated with an increase in the hazard of SCD (HR 1.53, 95% CI 1.29-1.81, p<0.0001). Using cubic splines, the HR for SCD increased as UVMmax increased (Figure B). A minority of participants with the highest UVMmax values had SCD risk that was 4-5 times that of participants with UVMmax of ~10 μV.

Conclusions:
Larger U-waves as assessed vectorcardiographically by higher UVMmax are independently associated with SCD in a large community based cohort. VCG analysis of the U wave is useful, and further study of the association between U waves and ventricular arrhythmias/SCD is warranted.
Abstract 13097: Flow and Cardiac Output Redistribution in the Fetus With {S,D,D} Transposition of the Great Arteries and Intact Ventricular Septum: Insights Into the Pathophysiology
Authors: Godfrey Max E , Friedman Kevin G , Drogosz Monika , Rudolph Abraham M , Tworetzky Wayne
Published: April 2024

Introduction:
Although the postnatal physiology of {S,D,D} transposition of the great arteries with intact ventricular septum (TGA) is well established, little is known about fetal TGA. In the normal fetus, the pulmonary valve (PV) is larger than the aortic valve (AoV), there is exclusive right to left flow at the foramen ovale (FO) and ductus arteriosus (DA), and the left ventricle (LV) ejects 40% of combined cardiac output (CCO) through the aorta, primarily to the brain. In TGA, the LV ejects O
2
-rich blood to the pulmonary artery, theoretically leading to pulmonary vasodilation, increased branch pulmonary arterial flow and resultant reduced DA flow. We tested the hypothesis that TGA anatomy results in altered distribution of CCO, FO and DA flow, and valve size.

Methods:
We analyzed valve size, color flow and pulse Doppler on echocardiograms of 74 fetuses with TGA (2003-2015). Findings were compared with our institutional normal fetal data, n=222.

Results:
The LV component of CCO was higher in TGA than in controls (50.7% vs 40.2%, p<0.001) with no difference in total CCO. Flow was bidirectional at the FO in 56 (75.7%) fetuses and at the DA in 24 (32.4%). Only 21.6% had normal exclusive right to left flow at both shunts. Bidirectional shunting was more common in the 3
rd
trimester than the 2
nd
(p<0.03). In contrast to normal, TGA AoV and PV sizes were nearly identical, hence the AoV z-score was higher than the PV z-score (1.13 vs -0.65, p<0.001).

Conclusion:
In TGA there is loss of normal right sided dominance, as each ventricle provides half of the CCO. The AoV is relatively large as it carries 50% of CCO rather than the normal 40%. The PV is relatively small as it carries 50% rather than the normal 60% of CCO. There is increased LV component of CCO (to the pulmonary arteries) and frequently bidirectional FO and DA flow. This may support the theory that high pulmonary arterial O
2
content lowers pulmonary vascular resistance, thereby increasing branch pulmonary arterial flow and venous return, increasing LV preload and output. Pulmonary sensitivity to O
2
is thought to increase later in gestation, which may explain the increased bidirectional shunting. Consequences of these flow alterations include increased aortic and likely brain flow, perhaps compensating for substrate deficiency in TGA.
Abstract 13102: Microrna-150 Modulates Ischemia-induced Neovascularization in Atherosclerotic Conditions
Authors: Desjarlais Michel , Sylvie Dussault , Dhahri Wahiba , Mathieu Raphael , Rivard Alain
Published: April 2024

Background:
Hypercholesterolemia is an atherosclerotic condition that is associated with impaired neovascularization in response to ischemia. This study sought to define the role of microRNAs (miRNAs) in that pathophysiology.

Methods and results:
Next generation sequencing and qRT-PCR analyses identified miR-150 as a pro-angiogenic miRNA which expression is significantly reduced in the ischemic muscles of hypercholesterolemic ApoE-deficient (ApoE
-/-
) mice, and in HUVECs exposed to oxLDL. Forced expression of miR-150 using a miR mimic could rescue oxLDL-mediated impairment of endothelial cell migration and tubule formation in vitro. In a mouse model of hindlimb ischemia, intramuscular injection of miR-150 mimic restored blood flow recuperation, vascular densities in ischemic muscles, and functional mobility in ApoE
-/-
mice. Treatment of ApoE
-/-
mice with miR-150 also increased the number and the activities of pro-angiogenic cells (PACs). miR-150 targets SRC kinase signaling inhibitor 1 (SRCIN1), an important regulator of Src activity. Here we found that hypercholesterolemia and oxLDL exposure are associated with increased SRCIN1 expression and decreased Src activity. However, treatment with miR-150 mimic reduces SRCIN1 expression and restores Src and downstream eNOS and Akt activities both in vitro and in vivo. We also demonstrate that the angiogenic effects of miR-150 are abolished when endothelial cells are treated with an inhibitor of Src.

Conclusions:
Hypercholesterolemia is associated with reduced expression of miR-150, impaired Src signaling and inefficient neovascularisation in response to ischemia. Forced expression of miR-150 using a miR mimic could constitute a novel therapeutic strategy to improve ischemia-induced neovascularization in atherosclerotic conditions.
Abstract 13127: Catheter Ablation of Atrial Fibrillation: Midterm Outcome of Radiofrequency Catheter Ablation for Redo Procedures After Pulmonary Vein Isolation With the Cryoballoon First Versus Second Generation Cryoballoon)
Authors: Kettering Klaus , Gramley Felix
Published: April 2024

Introduction:
Catheter ablation has become the first line of therapy in patients with symptomatic, recurrent, drug-refractory AF. Cryoablation has been shown to be a safe and effective technique for PV isolation. However, there is a significant arrhythmia recurrence rate after cryoablation procedures and there are no established strategies for redo procedures in these patients. Therefore, we have summarized our experience with radiofrequency catheter ablation for redo procedures after pulmonary vein isolation with the cryoballoon technique (ater procedures performed with the first or second generation cryoballoon).

Hypothesis / Methods:
Sixty patients had to undergo a redo procedure after initially successful circumferential PV isolation with the cryoballoon technique (Arctic Front Balloon, Medtronic: 30 patients (group A); Arctic Front Advance, Medtronic: 30 patients (group B)). The redo ablation procedures were performed using a segmental approach or a circumferential ablation strategy (CARTO) depending on the intra-procedural findings.

Results:
During the redo procedure, a mean number of 1.9 re-conducting PVs were detected (group A: 2.5 re-conducting PVs, group B: 1.3 re-conducting PVs). In 26 patients in group A, a segmental approach was sufficient to eliminate the residual PV conduction because there were only a few recovered PV fibers (1-3 reconnected PVs; group A1). In the remaining 4 patients in group A, a circumferential ablation strategy was used because of a complete recovery of the PV-LA conduction of all four PVs (group A2). In group B, a segmental approach was sufficient in all patients because there was only a minor reconnection of 1-2 PVs. All recovered PVs could be isolated sucessfully again. At 6-month follow-up, 80.0 % of all patients were free from an arrhythmia recurrence (48/60 patients; group A: 23/30 patients (76.7 %), group B: 25/30 patients (83.3 %)).

Conclusions:
In patients with an initial circumferential PVI using the cryoballoon technique, a repeat ablation procedure can be performed safely and effectively using RF catheter ablation. In most cases only a few re-conducting PV fibers were found and therefore, a segmental re-ablation approach seems to be sufficient in the majority of patients.
Abstract 13189: Traumatic Bleeding Severity Score (TBSS) based Initiation of Massive Transfusion Results in Earlier Transfusion and Improved Outcomes in Severely Injured Trauma Patients With Hemorrhagic Shock: A Prospective Interventional Study
Authors: Ogura Takayuki , Lefor Alan K , Fujizuka Kenji , Nakamura Mitsunobu , Nakano Minoru
Published: April 2024

Introduction:
The Traumatic Bleeding Severity Score (TBSS) classifies the need for massive transfusion (MT) in severely in cured trauma patients. We showed that 95% of trauma patients with TBSS >/= 17 need MT (Fig. 1, 2A). We hypothesized that the TBSS-guided activation of MT protocol can achieve early initiation of transfusion and improve the outcome of trauma patients with hemorrhagic shock.

Methods:
A single center prospective, interventional, and observational study was performed, which enrolled trauma patients admitted from 2013 to 2015 (TBSS-guided). In this group, the MT protocol was activated with a TBSS >/= 17 (Fig. 2B). Outcomes were compared with historical controls (2010-2012) who underwent MT, initiated without specific guidance (No-guidance). Patients resending in cardiac arrest or diagnosed with severe brain injury (GCS<6) were excluded.

Results:
A total of 119 patients were enrolled. The TBSS-guided group included 47, with 72 in the No-guidance group. There was no significant difference between the groups regarding injury severity score, vital signs, amount of transfusion, transfusion ratio ( red blood cells / fresh frozen plasma), and TBSS. In the TBSS-guided group, the time from admission to activation of MT protocol was shorter (100.1 minutes vs 32.7 minutes, p<0.001), the calculated probability of survival was lower (85.6% vs 75.0%, p=0.026), but observed 30-day survival was higher (91.5% vs 69.4%, p=0.004), compared to the No-guidance group.

Conclusion:
TBSS based initiation of MT results in earlier transfusion and improved outcomes of severely injured trauma patients with hemorrhagic shock.
Abstract 13228: SUMO2 Induces Cardiac Hypertrophy
in Vivo
and
in Vitro
, Independent of Sumoylation
Authors: Bernt Alexander , Rangrez Ashraf Y , Eden Matthias , Rohr Claudia , Katz Sylvia , Jungmann Andreas , Williams Tatjana , Ritter Oliver , Müller Oliver J , Katus Hugo A , Frank Derk , Frey Norbert
Published: April 2024

Introduction:
The calcineurin (Cn)-NFAT signaling axis is a pivotal pathway in cardiac physiology and pathophysiology including remodeling and pathological hypertrophy.

Methods and results:
We have previously shown that SUMO2 (S2) is a strong activator of Cn-NFAT signaling and, furthermore, is a direct interaction partner of Cn. S2 is sufficient and necessary to induce cardiomyocyte hypertrophy in NRVCMs. Interestingly, a sumoylation-deficient mutant of S2, S2ΔGG, yielded similar results in every parameter investigated. Overexpression of S2 or S2ΔGG enhances nuclear CnA localization as evidenced by subcellular fractionation as well as immunofluorescence experiments. The direct interaction of S2 and CnA is further supported by proximity-ligation-experiments in NRVCM. Additionally, knockdown of Ubc9, the sole E2-enzyme in the sumoylation cascade, had no significant influence on S2‘s effects, further supporting a sumoylation-independent mechanism. Knockdown of S2 revealed its necessity for agonist induced hypertrophy as shown by an abrogation of phenylephrine induced hypertrophy (median cell size: miRNeg+PE=512 μm
2
, miRS2+PE=519 μm
2
, n>3000 cells) and diminished expression of fetal genes and Rcan-1.4 (miRNeg+PE vs. miR-S2+PE:
Nppa
: -41%,
Nppb
: -57%,
Rcan1.4
: -80%; p<0.001, n=6).

On the basis of these
in vitro
findings, we designed an AAV9 gene transfer approach for S2 and S2ΔGG in mice, as a proof-of-principle for the
in vivo
relevance of this mechanism. In line with the proposed mechanism, both S2 constructs induced cardiac hypertrophy with elevated heart weight to body weight ratio (+25%, p<0.05; n=6 mice) and increased lung weight to body weight ratio (+20%, p<0.05) as a sign of heart failure. Consistent with pathological hypertrophy, fractional shortening (FS) and ejection fraction (EF) were reduced (FS, Ctrl: 25%, S2: 19%, S2ΔGG: 20%; p<0.05; EF: Ctrl: 37%, S2: 26%, S2ΔGG: 30%; p<0.01). Furthermore these animals showed elevated
Nppb
(S2: 2.7-fold, S2ΔGG: 2.4-fold; p<0.01) and
Rcan1.4
levels (S2: 4.5-fold, S2ΔGG: 5.5-fold; p<0.01).

Conclusions:
We propose a mechanism where S2 causes cardiac hypertrophy, independent of sumoylation, by a direct interaction with calcineurin A, facilitating its translocation to the nucleus.
Abstract 13411: Outcomes Associated With Warfarin Time in Therapeutic Range among Veterans With Nonvalvular Atrial Fibrillation in the US, 2005-2015
Authors: Liu Shuqian , Li Xiaoyan , Shi Qian , Hamilton Melissa , Friend Keith , Zhao Yingnan , Horblyuk Ruslan , Hede Shalini , Shi Lizheng
Published: April 2024

Introduction:
This study evaluated the relationship between quality of warfarin control and clinical outcomes among US veterans with nonvalvular atrial fibrillation (NVAF).

Hypothesis:
Poor quality of warfarin control (time in therapeutic range (TTR) <65%) is associated with reduced effectiveness and safety.

Methods:
Using the US Veterans Affairs electronic medical records database, patients with NVAF who newly initiated warfarin from 1/1/2005-12/31/2015 were grouped into two cohorts based on TTR <65% or ≥65%. TTR was computed from international normalized ratio test results comprehensively recorded in the database. Clinical outcomes assessed in the study were stroke/systemic embolism (SE), hemorrhagic stroke, ischemic stroke, and major bleeding, defined based on hospitalization with those conditions as primary diagnosis, as well as all-cause mortality. Patients were followed from warfarin initiation to the first occurrence of an outcome or censoring. For each outcome, unadjusted and adjusted hazard ratios (HR and aHR) between two cohorts were estimated, with the latter from propensity score weighting-adjusted time-varying Cox proportional hazard regression stratified by CHA
2
DS
2
-VAS
C
score (≥2 or not), controlling for setting of warfarin initiation, baseline patient demographic and clinical characteristics, and use of co-medications.

Results:
A total of 127,385 patients with NVAF (mean age (SD): 71.3 (9.8) years, 99% male) with a median of 1.4 follow-up years (IQR: 3.3) were included. Mean TTR was 51%. TTR<65% was observed in 65% of patients. Mean CHA
2
DS
2
-VAS
C
score (SD) was 2.9 (1.5) in low TTR cohort and 2.7 (1.4) in high TTR cohort. Low TTR cohort (with mean TTR as 38%) had significantly higher risk for assessed outcomes compared with high TTR cohort (with mean TTR as 77%) (Table).

Conclusions:
In the study, the observed quality of warfarin control among US veterans with NVAF was suboptimal and associated with elevated risk of adverse clinical outcomes.
Abstract 13433: Coping Partnership Intervention Improves Heart Failure Self-Care Confidence and Reduces Unplanned Healthcare Utilization
Authors: Graven Lucinda J , Gordon Glenna , Bahorski Jessica , Grant Keltner Joan
Published: April 2024

Introduction:
Social support and social problem-solving, as coping resources, are related to HF self-care, but interventions which target these resources to enhance HF self-care and reduce unplanned emergency room visits and hospitalizations are lacking.

Purpose:
To determine the efficacy of a nurse-led telephone coping partnership intervention on HF self-care and unplanned healthcare utilization in patients with HF.

Methodology:
A 3 group randomized controlled pilot study was conducted with 107 HF patients for 3 months. The 12-week coping intervention (
n
= 34) included 1 home visit, weekly telephone calls for month 1, and biweekly calls for months 2 and 3. The attention group (
n
= 38) received telephone calls starting at week 2 which followed the same pattern as the intervention group. All groups received usual care, with the control group (
n
= 35) receiving usual care only. Characteristics of HF patients were: mean age 61 years; 54.2% male; 54.2% African American; and NYHA I: 8.4%; II: 43.9%; III: 18.7%; IV: 29%. All groups provided data at baseline, 5 weeks, 9 weeks, and 13 weeks. HF self-care was assessed using the Self-Care of Heart Failure Index. Data analysis included descriptive statistics and linear mixed modeling.

Results:
A total of 64 patients completed the study (18 intervention; 24 attention; 22 control). Three linear mixed models were built, controlling for covariates (e.g., gender, race, marital status, NYHA HF class). No significant effects over time were noted by group for self-care maintenance and self-care management. However, significant effects over time were noted for self-care confidence in the intervention group (
p
= .030). Patients in the intervention group also reported fewer emergency room visits at 13 weeks (5.6% versus 8.3 % attention; 27.3% control), as well as fewer hospitalizations (5.6% versus 12.5% attention; 27.3% control).

Conclusions:
Nurse-led telephone coping partnership interventions that strengthen support and social problem-solving appear to be most effective in improving self-care confidence and in reducing unplanned healthcare utilization in individuals with HF. Future research should explore the influence of other variables (e.g., dyadic relationship) on HF outcomes using telephone coping partnerships.
Abstract 13491: Mitral Valve Annular Dilatation & Augmented Valve Closing Force to Tract Papillary Muscle as a Possible Mechanism of Late-systolic Mitral Valve Prolapse: Pre- & Post-operative Echocardiographic Study With Speckle Tracking Analysis
Authors: Fukuda Shota , Song Jae-Kwan , Mahara Keitaro , Abe Yukio , Jang Jeong Yoon , Kuwaki Hiroshi , Hayashi Atsushi , Onoue Takeshi , Hei Soshi , Iwataki Mai , Sun Byung Joo , Kim Yun Jeong , Takeuchi Masaaki , Eto Masataka , Nishimura Yosuke , Sasaki Yasuyuki , Takanashi Shuichiro , Levine Robert A , Otsuji Yutaka
Published: April 2024

Introduction:
Stable papillary muscle (PM) position and contraction enable constant PM tip distance from mitral valve (MV) annulus, which can contribute to constant MV coaptation height during systole (Figure A).

Hypothesis:
In patients with late-systolic MV prolapse (L-MVP), superior shift of MV coaptation toward left atrium (LA) during systole may be linked to abnormal PMs superior shift, which can be related to augmented MV closing force by MV annular dilatation.

Methods:
In 15 controls and 20 with L-MVP, MV coaptation height from its annulus was measured at early- and late-systole by echocardiography to evaluate systolic superior shift of MV coaptation. Distances of PMs tip and MV annulus from external reference point around the apex were monitored by 2 points speckle tracking, and systolic shift of PMs tip toward MV annulus was measured (Figures B and C). MV closing force was calculated as MV annular area х (systolic blood pressure - 10). Echocardiography was repeated after MV plasty in 5 L-MVP patients.

Results:
Systolic superior shift of MV coaptation (3.3±0.9 vs 1.4±0.5 mm/m
2
) and PMs tip (2.9±1.3 vs 1.3±0.4 mm/m
2
) relative to MV annulus were greater in L-MVP compared to controls (p<0.001) (Figures C and D). Systolic superior shift of MV coaptation was independently determined by systolic superior shift of PMs tip (β=0.66, p<0.001), which was related to augmented MV closing force with MV annular dilatation (β=0.72, p<0.001). Systolic superior shift of PMs tip (4.2±2.0 to -0.5±1.2 mm/m
2
, p=0.007) and MV coaptation (4.2±1.7 to 0.9±0.3 mm/m
2
, p=0.006) disappeared after surgical MV plasty with reduction in MV annulus and MV closing force in 5 patients with L-MVP.

Conclusions:
Systolic superior shift of MV coaptation in patients with L-MVP was associated with systolic superior shift of PM tip. Disappearance of these abnormalities after surgical MV plasty suggests that primarily augmented MV closing force with MV annular dilatation acting on PM traction may promote L-MVP.
Abstract 13507: Inappropriate Preoperative Stress Testing is Common Across Medical Specialties: A Single-Center Review
Authors: Peterson Brandon , Ghahramani Mehrdad , Emerich Matthew , Pinto Benjamin , Devine Michael , Foy Andrew
Published: April 2024

Introduction:
According to appropriate use criteria, preoperative stress testing in asymptomatic patients is considered “rarely appropriate” in patients with: 1) moderate to good functional capacity (≥4 METs), 2) no clinical risk factors, or who are 3) asymptomatic following revascularization, normal stress test, or normal coronary angiography within one year. Stress testing is also not recommended in patients estimated to be low-risk (<1%) for adverse cardiac events according to ACC/AHA guidelines.

Hypothesis:
We hypothesized that cardiologists, when compared with other specialties, would be less likely to order preoperative testing in low-risk patients or for rarely appropriate indications.

Methods:
We reviewed preoperative stress tests for non-cardiac surgery performed at Hershey Medical Center from January 2012 through December 2014. Stress tests performed for solid organ transplant evaluation were excluded. Chi square analysis was used to compare frequencies of test appropriateness and patient risk. Risk for adverse cardiac events was estimated using the National Surgical Quality Improvement Program (NSQIP) Myocardial Infarction and Cardiac Arrest (NSQIP MICA) risk calculator.

Results:
505 preoperative stress tests meeting study criteria were analyzed. Out of 219 preoperative stress tests ordered by cardiologists, 121 (55%) were classified as “rarely appropriate”, compared with 217 of 286 stress tests (76%) ordered by other specialties (p<0.0001). Median cardiac risk for 361 patients with sufficient data to estimate by NSQIP MICA was 0.6% (interquartile range 0.4-1.2%). 248 of 361 stress tests (69%) were performed on patients estimated to be low-risk. Frequency of low-risk testing did not significantly differ (p=0.32) between cardiologists (96 of 146, 66%) and other specialties (152 of 215, 71%).

Conclusions:
Cardiologists were significantly less likely to order rarely appropriate stress tests compared with other specialties. The majority of stress tests ordered by cardiologists and by other specialties, however, were rarely appropriate and in patients at low-risk (<1%) for cardiac complications. Interventions to reduce inappropriate preoperative stress testing, therefore, require a multispecialty approach.
Abstract 13745: Heart Failure is Associated With Depletion of Core Intestinal Microbiota
Authors: Winkler Thorben , Luedde Mark , Heinsen Femke-Anouska , Ruehlemann Malte C , Spehlmann Martina E , Bajrovic Amer , Lieb Wolfgang , Franke Andre , Ott Stephan J , Frey Norbert
Published: April 2024

Introduction:
Despite current medical treatment approaches, mortality of chronic heart failure (HF) remains high. Novel treatment modalities are thus urgently needed. A recent theory proposes a possible impact of the intestinal microbiome on the incidence and clinical course of HF. This study sought to investigate, if there are specific changes of the intestinal microbiome in HF patients.

Methods and Results:
The intestinal microbiome of 20 patients with HF with reduced ejection fraction due to ischemic or dilated cardiomyopathy was investigated applying high-throughput sequencing of the bacterial 16S rRNA gene. Microbial profiles were compared to those of healthy matched controls (n=20). According to the Shannon diversity index (measuring the intra-individual alpha-diversity) based on the distribution of operational taxonomic units, HF cases showed a nominally significantly lower diversity index compared to controls (P
nom.
=0.01), testing for genera abundance showed a tendency towards a decreased alpha diversity of HF patients. Beta-diversity measures (inter-individual diversity) revealed a significant separation of HF cases and controls, (e.g. P
weighted UniFrac
=0.004). Assessing the individual abundance of core measurable microbiota, a significant decrease of
Coriobacteriaceae
,
Erysipelotrichaceae
and
Ruminococcaceae
was observed on the family level. In line,
Blautia
,
Collinsella
,
Erysipelotrichaceae
and
Ruminococcaceae
showed a significant decrease in HF cases on the genus level.

Conclusions:
HF patients showed a significantly decreased diversity of the intestinal microbiome as well as a downregulation of key intestinal bacterial groups. Our data point to an altered intestinal microbiome as a potential target in the pathogenesis and progression of HF.

Figure:
Differences of taxonomic groups between HF pat. and controls. ns: not significant (p>0.05), *: p<0.05, **: p<0.01, ***: p<0.001. before/after correction for multiple testing.
Abstract 13819: Delayed Enhancement Cardiac Magnetic Resonance Imaging Predicts Response to Cardiac Resynchronization Therapy
Authors: Khan Akbar H , Gage Ryan M , Bajpai Ambareesh , Syed Imran S , Burns Kevin V , Bank Alan J
Published: April 2024

Introduction:
Primary predictors of cardiac resynchronization therapy (CRT) are based on conduction system characteristics, such as QRS duration and morphology. The ability of MRI to predict CRT response is less understood.

Methods:
We studied 83 patients who received cardiac MRI with gadolinium delayed enhancement (DE) prior to CRT. Patients had preCRT EF ≤ 40%, preCRT QRS ≥ 120ms, and paired ~1 year postCRT echocardiograms. MRIs were read without knowledge of patient characteristics or CRT outcomes and echocardiograms were read in a core-lab blinded to MRI results.

Results:
Patients were classified as having no DE (n=27), only septal midwall DE (n=20), or scar / DE (transmural, subendocardial, or subepicardial) (n=36). Prior to CRT, those with septal midwall DE (25 ± 7) had lower EFs than those with scar / DE (31 ± 6, p=0<0.01), but not statistically different from those without DE (29 ± 6). Those without DE had better (p<0.001) EF (14.2 ± 10 units) and LVESV improvements (-42 ± 21%) following CRT than those with midwall DE (EF: 2.1 ± 9 units; LVESV: -3 ± 35%) or those with scar / DE (EF: 1.4 ± 8 units; LVESV: -5 ± 25%). There was no difference in CRT response between non-ischemics with septal midwall DE and patients with scar / DE. In univariate regression models LBBB tended (p=0.12) to predict a beneficial EF response to CRT while presence of midwall DE was highly significant (p<0.001) for predicting a lack of response in the 47 patients without scar. In a multivariate model including many baseline characteristics, septal midwall DE provided predictive value (p<0.001) for EF response whereas the common predictors of gender (p=0.693) and LBBB (p=0.913) did not.

Conclusions:
DE cardiac MRI is a good predictor of response to CRT. The absence of any DE predicts a significant improvement in EF and LV volumes. In the idiopathic non-ischemic population the presence of septal midwall DE was a better negative predictor of response than more traditional characteristics of LBBB and gender. In addition, the presence of transmural, subendocardial, or subepicardial scar also predicted lack of improvement in LV function and volumes with CRT. The information obtained from DE MRI could help determine which patients would be best helped by CRT.
Abstract 13832: GPR39 is a High Affinity Vascular Smooth Muscle Receptor for P450 Eicosanoids
Authors: Alkayed Nabil , Cao Zhiping , Qian Zu Yuan , Xie Fuchun , Li Bingbing , Xiao Xiangshu , Barnes Anthony , Kaul Sanjiv
Published: April 2024

Epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic acids (HETEs) are endogenous vasoactive P450 eicosanoids that play important roles in cardiovascular physiology and disease, but their mechanisms of action are not fully understood. We developed a clickable photo-crosslinking probe (EET-P) based on EETs regio-isomer 14,15-EET, which allowed us to purify and enrich 14,15-EET binding proteins in mouse heart vascular smooth muscle cells (VSMCs). Proteomic analysis generated a list of proteins bound by EET-P that included the orphan G-protein coupled receptor 39 (GPR39). Consistent with the molecular weight of GPR39, sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) analysis revealed a prominent ~50 kD protein crosslinked to EET-P, and pretreatment with either 14,15-EET or its antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) completely displaced EET-P binding. Heterologous expression of GPR39 but not a control plasmid in HEK293 cells conferred responsiveness to both 14,15-EET and 15-HETE, as assayed by extracellular-regulated kinase (ERK) activation. Immuno-histochemical analysis localized GPR39 expression in both mouse heart micro-vessels and primary cultured VSMCs. Live-cell imaging of VSMC intracellular calcium ([Ca
2+
]i) revealed a dual and antagonistic regulatory mechanism in which 15-HETE induces and 14,15-EET suppresses VSMC calcium transients. Short hairpin RNA (shRNA) knockdown of GPR39 in VSMCs was sufficient to abolish effects of both 15-HETE and 14,15-EET on VSMC calcium. Our results identify GPR39 as a high-affinity, lipid-sensing GPCR antagonistically regulated by two endogenous P450 eicosanoids with opposing actions on VSMC calcium, and offer a unique window into multi-ligand GPCRs and their role in integrating the multitude of hormonal signals to regulate local tissue function and response to disease state.
Abstract 13834: Changes in Treatment Patterns and Incremental Healthcare Utilization Due to P2Y
12
Associated Disorders in Patients With Acute Coronary Syndrome
Authors: Vyas Ami , Bash Lori D , Patel Mehul D , Simpson Ross J
Published: April 2024

Introduction:
Data on the effect of P2Y
12
associated disorders on adherence to antiplatelet therapy (APT) in acute coronary syndrome (ACS) patients are sparse. We describe the characteristics, treatment patterns, associated disorders and healthcare utilization (HU) among ACS patients on P2Y
12
APT.

Methods:
Patients age ≥18 discharged from an ACS hospitalization in 2012-2014 who initiated P2Y
12
APT (ticagrelor, prasugrel, or clopidogrel) were identified from the MarketScan commercial claims database. The proportion of patients within each treatment group who experienced P2Y
12
associated disorders within one year, and who were adherent to APT were determined. Adjusted poisson regressions estimated the association between P2Y
12
non-adherence and HU (hospitalization, emergency visits, outpatient visits, cardiac events, transfusions).

Results:
Among 11,629 ACS patients, most were male, 45% had hypertension and 21% had diabetes. Clopidogrel use was common, and ticagrelor less common. Among all groups, about a third experienced P2Y
12
associated disorders. One-year adherence to APT was suboptimal (68%) and highest among prasugrel users (71%); switching was most common in ticagrelor users. Non-adherent patients experienced 1.34, 1.09, and 1.85 (p<0.05) times as many hospitalizations, emergency room visits, and transfusions, respectively, compared to adherent patients. Also, patients not adherent to ticagrelor experienced 1.9 times as many cardiac events as adherent patients. However, this association was not significant for clopidogrel or prasugrel users.

Conclusions:
P2Y
12
associated disorders were common. Adherence was suboptimal and non-adherence was associated with increased HU. Disease management strategies to improve adherence and reduce treatment-associated adverse events through individualized patient care, alternative secondary treatment options and physician awareness should be assessed.
Abstract 13842: Association of CHADS2VASc Score and Warfarin Use With Thromboembolic Risk Among HIV-Infected Persons With Atrial Fibrillation
Authors: Chau Katherine H , Scherzer Rebecca , Hsue Priscilla Y , Shlipak Michael
Published: April 2024

Introduction:
The prevalence of atrial fibrillation in the human immunodeficiency virus (HIV)-infected population is growing, but the association of the CHADS2VASc score with thromboembolic (TE) risk is unknown in this population.

Objective:
We evaluated the association of the CHADS2VASc score with TE events in HIV patients with atrial fibrillation, and the effectiveness of warfarin for TE prevention.

Methods:
Within the Veterans Affairs HIV Clinical Case Registry, 914 patients had an atrial fibrillation diagnosis between 1997-2011 with no prior TE events. We compared TE incidence by CHADS2VASc scores, overall and stratified by warfarin use. Using Cox proportional hazards regression, we modeled associations of CHADS2VASc scores and warfarin use with TE risk.

Results:
At baseline, the number of patients with CHADS2VASc scores of 0, 1, and 2+ were 208, 285, and 421 respectively; 36 patients developed TE events during a median of 3.8 years follow-up. Unadjusted event rates for CHADS2VASc score groups of 0, 1, and 2+ were 5.4, 10.0, and 8.7 per 1000 person years, respectively (hazard ratio [HR]=1.83 [95% confidence interval {CI} 0.71, 4.73] for CHADS2VASc score 1 versus 0,
p
=0.21; HR=1.43 [95% CI 0.55, 3.69] for CHADS2VASc score 2 or higher versus 0,
p
=0.46). Warfarin use was significantly associated with increased risk of TE events, even after adjusting for CHADS2VASc scores (HR=2.15 [95% CI 1.05, 4.41],
p
=0.037). Warfarin use per year of exposure among current users had a HR of 2.64 for TE events (95% CI 1.28, 5.45;
p
=0.0089). Time-updated warfarin use showed an even stronger association with increased risk of TE events (HR=6.07 [95% CI 2.95, 12.5],
p
<0.0001).

Conclusions:
In this national registry of HIV-infected veterans with atrial fibrillation, CHADS2VASc scores were only weakly associated with risk of TE events, and warfarin was not effective at preventing TE events and potentially harmful. These results should raise concerns about the optimal strategy for prevention of TE events among HIV-infected persons with atrial fibrillation.
Abstract 13848: Anatomic and Hemodynamic Changes in Single Ventricle Patients 3-9 Months After Fontan to the Teenage Years: Insights From Cardiac Magnetic Resonance and Computational Fluid Dyanmics
Authors: Fogel Mark A , Kim Esther , Harris Matthew , Whitehead Kevin , keller Marc , Spray Thomas , Gaynor J William , Fuller Stephanie , Mascio Christopher , Nicolson Susan , Montenegro Lisa , Diaz-Berenstein Laura , Trusty phillip , Wei Alan , Tree Michael , Yoganathan Ajit
Published: April 2024

Introduction:
Little is known of baseline cardiac magnetic resonance (CMR) data in single ventricle (SV) pts immediately after Fontan. In addition, total cavopulmonary connection (TCPC) changes from this point to the teen years may shed some light regarding how to optimize clinical outcome.

Hypothesis:
Anatomic, hemodynamic and computational fluid dynamic (CFD) parameters are significantly altered as pts age.

Methods:
SV pts 3-9 months after Fontan and teens were studied with CMR. Anatomy, flows and CFD modeling were performed. Significance = P<0.05.

Results:
22 were 3-9 months after Fontan (age 3±1.1 yrs, 0.6±0.3 yrs after Fontan) & 25 were teens (age 16±1.8 yrs, 14.1±2.2 yrs after Fontan). Although a higher indexed powerloss (iPL) in teens almost reached significance, Reynold’s number & particle resident time (time a red blood cell remains in the TCPC) were greater in teens than younger pts (table). Superior vena cava (SVC) pulsatility index (PI) was greater in younger pts while inferior vena cava (IVC) PI was greater in teens, owing to the primary caval return changing from SVC to IVC as pts age (table). Both cardiac index & caval return decreased in teens while hepatic flow distribution (HFD) became more evenly distributed in teens (table). The % TCPC stenosis at its narrowest point was greater in teens (42.8 %) than younger pts (20.9%), P=0.009. In teens, iPL (R=0.39) and % TCPC stenosis (R=0.62) correlated with time from Fontan (P<0.39 for both).

Conclusion:
In teens, iPL correlated with time from Fontan. Significant increase in particle resident time & Reynold’s number occur as SV pts age, with increased narrowing of the TCPC while HFD became more even. SVC PI is higher in younger pts while IVC PI is higher in teens. Cardiac index & caval return both decrease as pts age. These data serve as baseline information in the immediate post-operative state and may be used to aid in designing improved Fontan reconstruction to optimize clinical outcome.