bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13796: Global Longitudinal Strain (GLS) Predicts Progression to Severe Aortic Stenosis (AS) in Patients With Normal or Minimally Dysfunctional Bicuspid Aortic Valve (BAV)
Authors: Iskandar Aline , Pape Linda , Tighe Dennis , Aurigemma Gerard P
Published: April 2024

Background:
While prior research has documented the rate of progression of BAV to severe AS, myocardial function factors have received less attention. We hypothesized that reduced GLS might conceivably identify a high risk subset of BAV patients, as it has in other instances of severe valvular heart disease, such as chronic severe aortic regurgitation.

Methods:
We computed GLS (apical 2-, 3-, and 4-chamber views, Arena Software,TomTec) on baseline studies in two groups of pts with BAV. All had (1) EF ≥ 50%, (2) were free of wall motion abnormality and (3) were free of any significant valve dysfunction. Pts were followed for mean of 70 ± 18 months. In group 1 (STABLE) the BAV remained hemodynamically non-significant (absent or mild aortic regurgitation or stenosis) throughout follow-up and in group 2 (PROGRESS) the disease progressed from no or mild aortic disease to severe AS.

Results:
21 patients were included, 11 STABLE patients and 10 PROGRESS patients. Baseline characteristics were similar for the two groups (Table 1). All patients in PROGRESS had abnormal GLS (< -18%), whereas STABLE patients had GLS greater than -18%. GLS was significantly impaired in PROGRESS compared to STABLE (-15.9% vs -21.2%, p = 0.0001).

Summary:
1. Baseline GLS was impaired in patients who progressed from normal or mild aortic disease to severe aortic stenosis.

2. Baseline GLS was grossly within normal limits in those in whom the bicuspid aortic valve remained normal or minimally dysfunctional.

Conclusions:
A normal baseline GLS appears to predict a more benign course for patients with normal or minimally dysfunctional BAV, whereas a reduced GLS might identify a group at high risk for progression. Whether reduced baseline GLS relates to abnormalities in load or contractility, or signifies a ‘myocardial factor’ which is related to the BAV syndrome all remain to be elucidated.
Abstract 13830: Senescent CD8+ T Cells Are Increased and Associated With Clinical Outcome in Patients With Heart Failure
Authors: Youn Jong-Chan , Yu Hee Tae , Oh Jaewon , Park Sungha , Lee Sang-Hak , Choi Donghoon , Shin Eui-Cheol , Kang Seok-Min
Published: April 2024

Background:
The pathogenic role of T cells in heart failure (HF) has been well documented in recent animal studies. However, the existence of T cell driven inflammation in patients with HF has not been confirmed. Therefore, we studied immunologic characterization of T cells from patients with HF.

Methods:
We compared the frequency of senescent T cells in 23 end-stage HF patients (11 male, mean age 48 ± 13 years), 23 age- and sex-matched healthy control subjects (11 male, mean age 49 ± 12 years) and 17 newly diagnosed acute HF patients (8 male, mean age 59 ± 18 years) by multicolor flow cytometry. Senescent T cells were defined as CD28null or CD57+ cells in CD4+ or CD8+ T cell subset. Primary endpoint was cardiovascular (CV) events defined as CV mortality and rehospitalization due to HF aggravation.

Results:
The frequency of senescent CD8+ T cells was significantly increased in patients with end-stage HF compared to healthy control (CD8+CD57+ T cell fraction: 46.3 ± 22.3% vs. 29.0 ± 13.1%, p=0.003; CD8+CD28null T cell fraction: 47.7 ± 20.2% vs. 27.8 ± 12.1%, p<0.001). Regarding the newly diagnosed acute HF patients, patients with CV events showed significantly higher CD8+CD57+ T cell fraction compared with those with no CV events (46.5 ± 9.2% vs. 29.9 ± 11.5%, p=0.037).

Conclusion:
Senescent CD8+ T cells are increased and associated with clinical outcome in patients with HF, suggesting a role for T cell driven inflammation in HF. A more detailed characterization of senescent CD8+ T cells may offer new opportunities for the prevention and treatment of HF.
Abstract 13988: Novel Quantitative Assessment of Whole Blood Thrombogenicity in Patients Treated With Anticoagulants Undergoing Radiofrequency Catheter Ablation for Atrial Fibrillation
Authors: Ito Miwa , Kaikita Koichi , Sueta Daisuke , Ishii Masanobu , Arima Yuichiro , Iwashita Satomi , Takahashi Aya , Hoshiyama Tadashi , Kanazawa Hisanori , Sakamoto Kenji , Yamamoto Eiichiro , Tsujita Kenichi , Tsujita Kenichi , Tanaka Tomoko , Yamamuro Megumi , Kojima Sunao , Kojima Sunao , Hokimoto Seiji , Yamabe Hiroshige , Ogawa Hisao
Published: April 2024

Introduction:
Non-vitamin K antagonist oral anticoagulants (NOACs) are equivalent to warfarin in preventing thromboembolism in patients with atrial fibrillation (AF). Recently, Total Thrombus-formation Analysis System (T-TAS) was developed as an easy-to-use system for quantitative analysis of thrombus formation using microchips with thrombogenic surfaces (collagen, PL chip; collagen plus tissue factor, AR chip). Hypothesis: We evaluated the efficacy and safety of NOACs using the T-TAS in AF patients undergoing radiofrequency catheter ablation (RFCA).

Methods:
After exclusion of 19 from 121 consecutive patients undergoing RFCA for AF, the remaining 102 patients were divided into two groups; AF patients treated with warfarin (n=28), and NOACs (n=74). Blood samples obtained on the day (anticoagulant-free point), 3 days and 1 month after RFCA were used in T-TAS to compute the thrombus formation area under the curve (AUC) (PL24-AUC10, AUC for PL chip; AR10-AUC30, for AR chip). Results and Conclusion: The AR10-AUC30 and PL24-AUC10 levels were identical between the warfarin and NOACs groups on the day of RFCA (1708.5±162.1 vs 1757.5±138.0 in AR10-AUC30, p=0.13 and 389.1±95.5 vs 391.7±76.0 in PL24-AUC10, p=0.94, respectively). AR10-AUC30, but not PL24-AUC10 levels, was significantly lower in warfarin and NOACs groups at 3 days and 1 month after RFCA. Multiple logistic regression analysis identified AR10-AUC30 levels on the day of RFCA as a significant predictor of bleeding events in the period of three months after RFCA [odds ratio (OR) 20.6; 95% confidence interval (95%CI): 2.46 to 172.6; p=0.005]. Receiver-operating characteristic analysis showed that AR10-AUC30 levels on the day of RFCA significantly predicted bleeding events [AUC 0.849 (95%CI: 0.719-0.979; p<0.001)]. The cut-off levels of AR10-AUC30 were 1647.6 for identification of bleeding events within three months after RFCA. These results suggested that AR10-AUC30 level determined by T-TAS is a potentially useful marker for assessment of the efficacy and safety of anti-coagulant therapy including warfarin and NOACs, in AF patients undergoing RFCA.
Abstract 14023: Insulin-like Growth Factor-binding Protein 7 as a Biomarker of Diastolic Dysfunction and Functional Capacity: Results From the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction (RELAX) Trial
Authors: Gandhi Parul U , Redfield Margaret M , Chen Horng H , Stevens Susanna R , Anstrom Kevin J , Gaggin Hanna K , Semigran Marc J , Januzzi James L
Published: April 2024

Introduction:
Insulin-like growth factor-binding protein 7 (IGFBP7) was previously found to be associated with diastolic function in heart failure (HF) with reduced ejection fraction (EF), but it is unclear whether such associations exist in HF with preserved EF (HFpEF), where diastolic function is of pivotal importance.

Hypotheses:
Baseline (BL) and change (Δ) in IGFBP7 will be significantly associated and correlated with BL and Δ in diastolic indices as well as peak oxygen consumption (VO2
max
) in patients with HFpEF. IGFBP7 will decrease with sildenafil therapy.

Methods:
At BL and 6 months (6M), IGFBP7, imaging studies, and VO2
max
were obtained and compared in 160 HFpEF patients randomized to sildenafil or placebo.

Results:
Patients with supramedian BL IGFBP7 concentrations (>219 ng/mL) were more likely to be older, to have more congestion and worse renal function, and to have elevated concentrations of several emerging or established HF biomarkers including amino-terminal pro-B-type natriuretic peptide, cystatin C, and highly sensitive troponin (all P<0.05). Higher BL IGFBP7 was correlated with indices of worse diastolic function, including higher E velocity (ρ=0.395, P<0.001), E/e’ (ρ=0.398, P<0.001), left atrial volume index (ρ=0.386, P<0.001), right ventricular systolic pressure (RVSP; ρ=0.413, P<0.001), and transmitral E/A (ρ=0.258, P=0.006). IGFBP7 was also inversely correlated with aortic distensability (ρ= -0.301, P=0.02). There was no association or correlation with measures of systolic function. Notably, in analyses adjusted for respective baseline variables, ΔIGFBP7 was significantly correlated with Δ in E (ρ=0.114), E/A (ρ=0.225), E/e’ (ρ=0.174), and RVSP (ρ=0.282; all P<0.03). Elevated BL IGFBP7 was associated with lower BL VO2
max
(13.2 versus 11.1 mL/min/kg; P<0.001) and ΔIGFBP7 was inversely correlated with ΔVO2
max
(ρ=-0.19, P=0.01). Subjects receiving sildenafil had a decrease in IGFBP7 over 6M in contrast to placebo-treated patients (median ΔIGFBP7 -1.5 versus +13.6 ng/mL; P<0.001).

Conclusions:
In patients with HFpEF, concentrations of IGFBP7 have unique relationships with measures of diastolic dysfunction and VO2
max
. Rise in IGFBP7 may reflect worsening diastology and deteriorating VO2
max
.
Abstract 14263: Pyruvate Dehydrogenase Kinase 4 Leads to Reduced Endothelial-pericyte Interactions in Pulmonary Arterial Hypertension
Authors: Yuan Ke , Shao Ningyi , Hennigs Jan , Orcholski Mark , Richter Alice , Wu Joseph , de Jesus Perez Vinicio
Published: April 2024

Introduction:
Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by impaired angiogenesis, progressive small vessel loss and occlusive vasculopathy. Pericyte recruitment and establishment of endothelial-pericyte interactions is a critical event to ensure structural integrity and proper function of new vessels. Studies by our group and others have shown that establishment of endothelial-pericyte interactions is reduced in PAH and results in impaired but the mechanisms underlying this defect remain poorly understood. In an effort to identify relevant gene candidates associated with aberrant pericyte behavior, we performed a transcriptome analysis of healthy and PAH lung pericytes followed by computational network analysis.

Hypothesis:
PAH pericytes have increased genes involved in cell cycle progression, growth and motility.

Methods:
Pericytes were extracted from lungs of healthy (N=6) and PAH (N=6) patients followed by lineage validation using FACS and functional assays. RNA extracted from pericytes was converted into cDNA and used in Illumina microarrays. Expression of top candidate genes was validated in histological sections and purified lung using Taqman qPCR, western blot and immunofluorescence.

Results:
Pyruvate dehydrogenase kinase isozyme 4 (PDK4), which suppresses mitochondrial glucose oxidation in favor of anaerobic glycolysis, demonstrated the greatest upregulation in PAH pericytes. Compared to healthy cells, PAH pericytes had higher rate of glycolysis but reduced mitochondrial oxygen consumption and reactive oxygen species (ROS) production using Seahorse analysis. Treatment with PDK4 siRNA in PAH pericytes increased the rate of mitochondrial glucose oxidation, endothelial tube formation and motility.

Conclusions:
This is the first study demonstrating differences in gene expression profile that correlate with aberrant pericyte behavior during establishment of endothelial pericyte interactions in PAH. PDK4 inhibitor in PAH may reverse vascular remodeling and help protect against microvessel loss. Efforts to assess the relevance of other altered genes in PAH pericytes could lead to insights into PAH pathobiology and the identification of novel therapeutic targets.
Abstract 14577: Kvβ1.1 Binds Pyridine Nucleotides and Alters Cardiac Action Potential
Authors: Tur Jared , Badole Sachin L , Chapalamadugu Kalyan C , Tipparaju Srinivas M
Published: April 2024

Introduction:
Kvβ1 subunits demonstrate a unique ability to bind pyridine nucleotides and alter Kv channel function. Pyridine nucleotide levels are altered in cardiovascular diseases resulting in higher NADH levels. Therefore coupling of the Kvβ1 subunit with Kv channels may be important in how the repolarization is modulated in presence of NADH.

Hypothesis:
The Kvβ1 subunits are highly expressed in the heart and bind to multiple Kv channels (Kv4.x and Kv1.x) and regulate Kv channel activity. Therefore, we evaluated pyridine nucleotide changes in cardiovascular disease in the presence and absence of Kvβ1 and how they modulate Kv channel activity.

Methods:
Wild type (WT) and Kvβ1 knockout (KO) mice hearts (n=7 each group) using the
ex-vivo
Langendorff system were exposed to both acute and chronic alterations of lactate to induce an increase in NADH levels. Cardiac monophasic action potentials (MAPs) were measured before and 10 min after perfusion of the lactate, for chronic alterations mice were injected with isoprenaline to induce cardiac hypertrophy and demonstrated significant NADH increase. In addition we performed pull-down assays to identify binding partners of Kvβ1.1 in the heart.

Results:
We observed that, lactate exposure (10mmole/L) (
p
<0.05) prolonged left ventricular MAP duration in WT (9.4±0.7 vs. 15.6±1.2* at APD50) however KO mice demonstrated no significant difference (10.9±0.5 vs. 11.7±1.1). NADH levels in lactate exposed hearts demonstrated a 3 fold increase compared with control Krebs buffer. Lactate prolonged MAP durations in WT hearts, which was reversal by adding pyruvate (20mmole/L) to its control (pre-lactate; 8±0.5 vs. 13.6±0.6* vs. 8.4±0.6). The chronic model, MAP duration significantly (
p
<0.01) prolonged in the WT (9.7±0.7 vs. 15.3±1.1*) mouse hearts after isoprenaline infusion but not KO mouse (12.4±1.8 vs. 14.4±1). Immunoprecipitation experiments indicate that Kvβ1.1 interacts with Kv4.2 and Kv1.5 from mouse heart.

Conclusions:
Results obtained from this study suggested that the Kvβ1.1 subunit has the ability to sense redox changes including NAD/NADH alterations and modulate MAP through Kv activity. This study highlights the physiological role Kvβ1.1 plays in cardiac repolarization physiology and cardiac disease.
Abstract 14587: Proarrhythmic Effects of Ibrutinib, a Clinically Approved Inhibitor of Bruton’S Tyrosine Kinase (BTK) Used in Cancer Therapy
Authors: Yang Tao , Moslehi Javid J , Roden Dan M
Published: April 2024

Introduction:
Ibrutinib is a novel and potent BTK inhibitor which has been approved for several types of B-cell malignancies. Our meta-analysis of the published clinical trials finds that atrial fibrillation occurs in ~7% of patients after chronic ibrutinib exposure. Ventricular tachycardia has also been reported. Recently, multi-targeted tyrosine kinase inhibitors (TKIs) have been associated with arrhythmias; one implicated mechanism is increased late sodium current (INa-L) after chronic but not acute drug exposure. This effect appears to be mediated by inhibition of PI3Kinase since it is rescued by intra-pipette PIP3, a PI3K effector.

Hypothesis:
In this study, we tested the hypothesis that chronic exposure to ibrutinib exerts arrhythmogenic effects by this mechanism.

Methods:
Isolated adult mouse cardiac atrial/ventricular and rabbit ventricular myocytes as well as KCNH2 (HERG/Kv11.1)- or Kv4.3-transfected CHO cells were used for the electrophysiological studies pre- and post-ibrutinib (0.3 μ or 1 μM) acutely (5-10 min) and chronically (5 hrs in myocytes or 48 hrs in CHO cells). In some experiments, 1 μM PIP3 was added into the pipette solution.

Results:
Chronic but not acute ibrutinib prolonged cardiac action potentials (APs), triggered abnormal APs (EADs and DADs; Figure), and markedly increased cardiac INa-L (1.68±0.27% vs control 0.21±0.04% of peak current, P<0.01) in mouse atrial cells. A similar INa-L increase was also seen in mouse and rabbit ventricular cells. The abnormal APs and increased INa-L were antagonized by adding 1 μM PIP3 into the pipette and by the INa-L blocker ranolazine (10 μM). Ibrutinib has minor and no effects on cardiac HERG and Kv4.3 currents.

Conclusion:
Ibrutinib, like other TKIs, increased cardiac INa-L, an effect reversed by intracellular PIP3. These data further reinforce the importance of PIP3 signaling as a proximate mechanism leading to arrhythmogenesis by emerging targeted oncology therapies.
Abstract 14601: Vegetarianism is Independently Associated With Lower Risk of Left Ventricular Diastolic Dysfunction and Stage B Heart Failure Burden
Authors: Pai Ramdas G , Varadarajan Padmini , Jabo Brice , Maschak Andrew , Herring Patti , Fraser Gary E , Knutsen Synnpve F
Published: April 2024

Introduction:
Heart failure (HF) affects about 6 million Americans at an annual direct cost of $40 billion. Left ventricular (LV) diastolic dysfunction and stage B HF are predictors of clinical HF and reduction of stage B HF burden may help reduce HF disease burden in the community. In our Adventist Health Study-2 (AHS-2) of 96,000 subjects, a vegetarian compared to a non-vegetarian diet was associated with lower body mass index, and risk of diabetes and hypertension despite similar caloric intake.

Hypothesis:
We hypothesized that vegetarianism would also lead to a lower risk of LV diastolic dysfunction and stage B HF.

Methods:
We invited a random sample of 206 subjects from AHS-2 stratified by diet (vegetarians, lacto-ovo vegetarians, pescovegetarians and nonvegetarians), aged >60 years and living within 50 miles of Loma Linda for a clinic visit consisting of a history, anthropometrics, blood pressure measurement, food frequency questionnaire and a full echocardiogram. LV volume, EF, wall motion, diastolic function and mass and left atrial size were assessed based on guidelines of American society of Echocardiography.

Results:
The mean age was 74 (10) years, 49% were males and subjects were equally distributed in 4 food groups. LV diastolic dysfunction was present in 60%, LV hypertrophy in 10%, LVEF <50% in 5% and increased left atrial volume index in 45% of the subjects. After adjusting for age, gender, race, body surface area, prevalent MI, diabetes and hypertension, a vegan diet (no animal products), compared to non-vegetarian diet, was associated with a lower prevalence of LV diastolic dysfunction (OR 0.42, 95% CI 0.24-0.73) and LV hypertrophy (OR 0.30, 95% CI 0.08-0.86) Vegetarians also had a lower number of stage A risk factors and stage B components (p<0.05). There was a trend towards graded increase in risk of stage B HF with increasing degree of nonvegetarianism.

Conclusions:
A vegan diet is independently associated with lower risk of LV diastolic dysfunction, LV mass and stage B HF burden.
Abstract 14661: Early Predictive Markers of Right Ventricular - Pulmonary Vascular Dysfunction in Preterm Infants With Bronchopulmonary Dysplasia
Authors: Patel Meghna D , Levy Philip T , Dioneda Brittney , Sekarski Timothy J , Holland Mark R , Hamvas Aaron , Singh Gautam K
Published: April 2024

Introduction:
Improved survival of extremely preterm infants has led to an increased recognition of bronchopulmonary dysplasia (BPD) associated with abnormal cardio-pulmonary hemodynamics. Reliable non-invasive quantitative markers for early recognition of BPD in preterm infants are lacking. The aim of this study was to evaluate quantitative echocardiographic measures of right ventricular hemodynamics (RV) as early predictive markers in infants at risk for development of BPD.

Methods:
A prospective study was conducted in 115 preterm infants (< 29 weeks gestational age) enrolled through the Prematurity and Respiratory Outcomes Program (NCT01435187). Echocardiographic measures of RV function and pulmonary hemodynamics were evaluated at 32 and 36 weeks post-menstrual age (PMA). RV systolic function was assessed with fractional area of change (FAC), tricuspid annular plane systolic excursion (TAPSE), and global and free wall longitudinal strain. RV morphometrics were assessed with RV dimensions and areas. Pulmonary hemodynamics were assessed by pulmonary artery acceleration time (PAAT). Commonly used qualitative measures (tricuspid regurgitation velocity and septal flattening) were evaluated for comparison. BPD was classified by the NIH workshop definition.

Results:
RV global and free wall strain, FAC, TAPSE, and PAAT were significantly reduced, and RV morphometrics were significantly larger at 32 and 36 weeks PMA in preterm infants who developed BPD (Table 1). Qualitative measures were present in < 20% of patients, and only septal flattening was significant at 32 weeks PMA in the BPD group.

Conclusions:
Quantitative echocardiographic measures of RV function and pulmonary hemodynamics are reliable early predictive markers of subsequent development of BPD in preterm infants. These measures are superior to commonly used qualitative measures and can be useful tools for early identification of preterm infants at high risk for BPD.
Abstract 14857: Infarcted Hearts Respond Better to Cardiac Stem Cell Therapy After Pre-treatment With a Collagen Hydrogel
Authors: Maeda Kay , Rafatian Ghazaleh , Seymour Richard , Ruel Marc , Davis Darryl R , Suuronen Erik J
Published: April 2024

Background:
Cell therapy is a promising approach for repairing the injured myocardium. However, cells delivered too soon after myocardial infarction (MI) suffer from low retention and survival due to the harsh inflammatory post-MI milieu. In addition, autologous cells such as cardiac stem cells (CSCs) require time for isolation and culture prior to use, which precludes their delivery soon after MI. However, biomaterial therapy is not limited by these factors and can be applied in acute MI to limit myocardial damage. In this study, we treated the myocardium at the time of MI with a collagen matrix in order to prime the healing post-infarct environment and improve the efficacy of CSC therapy delivered late after MI.

Methods/Results:
C57BL/6J mice underwent LAD ligation to induce MI. Mice were then randomized to receive intramyocardial injection of PBS or matrix treatment at 3h post-MI, followed by PBS or 5х105 eGFP-CSCs at 7d post-MI. In total, 4 groups were evaluated: 1) 3h PBS/7d PBS (n=7), 2) 3h PBS/7d CSC (n=11), 3) 3h matrix/7d PBS (n=6) and 4) 3h matrix/7d CSC (n=12). Treatment with the matrix at 3h (groups 3 and 4) improved cardiac LVEF at 1wk post-MI (42.4±2.7%) compared to PBS-treated mice (groups 1 and 2; 37.9±3.7%; p=0.0004). After 4wk, the matrix/CSC treated mice (group 4) had superior LVEF (45.3±3.9%) compared to all other groups (29.4±3.9%, 35.9±2.5% and 40.1±4.0% for groups 1, 2 and 3, respectively; p≤0.02). Immunostaining for GFP+ cells revealed 1.5-fold greater CSC retention in the myocardium of matrix pre-treated mice (p=0.04). Vascular density (# of CD31+ capillaries/FOV) in the infarct area was 2.5-fold greater in PBS/CSC mice than in PBS-treated mice (group 1; p=0.001), and increased further in the matrix/CSC group (1.4-fold vs. group 2; p=0.03). The matrix/CSC treated mice (group 4) had significantly reduced scar size (% scar/total myocardial area) (by ≥40%; p≤0.002) and better preserved ventricular wall thickness (by ≥15%; p≤0.02) compared to all other treatment groups.

Conclusion:
Collagen matrix treatment in acute MI primes the injured heart to be more responsive to CSC therapy. This may constitute a plausible synergistic strategy to protect the myocardium and improve the benefits that can be achieved with cell therapy.
Abstract 14900: Impact of ICD Programming Changes to Avoid Inappropriate Shocks in the Young
Authors: Zimmerman Frank J , Bhan Aishwarya , Freter Anne , Shetty Ira , Russo Lisa , Dennis Janis , Zimmerman Frank T , Bhan Adarsh
Published: April 2024

Introduction:
ICD therapy in young pts has been shown to improve mortality but inappropriate ICD shocks (IAS) occur in up to 25% of young pts. Adult studies have shown that changing the VF detection rate (RATE) and/or duration to detection (DUR) results in fewer IAS without increasing mortality. The purpose of this study is to assess the impact of RATE and/or DUR changes to avoid IAS in young pts with ICDs.

Methods:
This two-part study initially consisted of a retrospective analysis of IAS in young pts with ICDs at our institution from 2007-2012. A total of 1200 intervals from EGMs recorded from 16 pts with IAS were analyzed and the risk for VF detection was calculated at various RATE and DUR. Analysis of true episodes of VT/VF in 8 pts was also performed. We found that changing the RATE from 200 bpm to 250 bpm resulted in a 49-85% reduction of risk for IAS. Based on this analysis, the RATE was increased to 220-250 bpm in our ICD pts from 2012-2015. The clinical rate of IAS was then compared before and after changing ICD programming to higher RATE.

Results:
64 pts (ages 8y to 57y, mean 21y, 41 male) were included in this study. In the time period from 2007-2012, IAS occurred in 30% of pts (50% due to lead malfunction and 50% due to SVT). ICD programming was changed to VF RATE of 220-250 bpm with DUR of 18/24 in all ICD pts in 2012 and thereafter. There was a significant reduction of IAS with ICD program changes (30% vs 1.5%, p=0.001) with no change in appropriate shock rate (APS) or lead malfunction rate between the two time periods (see table). There were no episodes of syncope or death in those with APS before or after programming changes.

Conclusions:
The incidence of IAS in young pts can be reduced by changes in ICD programming. Increasing the RATE has a greater impact on reduction of risk for IAS compared to prolonging DUR and did not result in an increase in syncope or death. These findings may help to standardize programming of ICDs in young pts.
Abstract 14944: Factor Xa Aggravates Atherosclerosis by Promoting Inflammasome Formation Through Suppressing Autophagy
Authors: Ito Yusuke , Maejima Yasuhiro , Tamura Natsuko , Watanabe Ryo , Isobe Mitsuaki
Published: April 2024

Introduction:
Growing body of evidence suggests that factor Xa (FXa), an endogenous coagulation factor, plays a critical role in promoting atherosclerosis. However, the mechanism how FXa facilitates atherogenesis remains unclear.

Hypothesis:
FXa promotes progression of atherosclerosis through protease-activated receptor-2 (PAR-2)-mediated modulation of autophagy machinery and innate inflammatory response.

Methods and Results:
Administration of 12 mg/kg/day of rivaroxaban (Riv), a direct FXa inhibitor, to the mice effectively elongated prothrombin time (Riv 12mg/kg/day: 14.6 ± 0.6*, Riv 6mg/kg/day: 9.2 ± 0.2*, Untreated: 7.1 ± 0.1 sec, *
P
< 0.05) and markedly suppressed plasma FXa activity (Riv 12mg/kg/day: 1.9 ± 0.1*, Riv 6mg/kg/day: 2.6 ± 0.3*, Untreated: 3.9 ± 0.3 RFU, *
P
< 0.05) compared with the mice treated with lower dose of Riv (6 mg/kg/day) or untreated mice. Riv treatment to ApoE
-/-
mice fed with a high-fat diet for 20 weeks markedly reduced the atherosclerotic areas in the sinus and whole aorta to 42.5 % (
P
> 0.05) and 50.4 % (
P
> 0.05), respectively. Moreover, Riv also reduced the inflammasome formation in the atherosclerotic lesions as evaluated by immunostaining of NLRP3.
In vitro
experiments using RAW264.7, a murine macrophage cell line, or mouse peritoneal macrophages demonstrated that treatment of 7-ketocholesterol (7KC), an atherosclerotic lesional oxysterol that promotes inflammation through inflammasome formation, significantly activated autophagy as evidenced by the increase in LC3-II protein and the number of autophagosomes. Treatment with FXa (50 nM) markedly induced phosphorylation of mTOR (Ser
2448
) and suppressed 7KC-induced autophagy, which was reversed in the presence of Riv (1 μM). In addition, Treatment with FXa significantly enhanced inflammasome formation induced by 7KC, which was blocked in the presence of Riv, as evaluated by the amount of NLRP3, caspase-1, and IL-1β. Importantly, however, treatment with FXa failed to block 7KC-induced autophagy and inflammasome activation in macrophages derived from PAR-2
-/-
mice.

Conclusion:
FXa positively regulates the atherogenesis, possibly through PAR-2-mediated pathway by inhibiting autophagy which, in turn, promoting inflammasome activation in macrophages.
Abstract 14955: Factors Associated With High Contrast Utilization During Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary Multicenter Registry
Authors: Christakopoulos Georgios E , Christopoulos Georgios , Karmpaliotis Dimitri , Alaswad Khaldoon , Yeh Robert W , Jaffer Farouc A , Wyman Michael R , Lombardi William , Grantham Aaron , Kandzari David , Lembo Nicholas , Moses Jeffrey W , Kirtane Ajay , Parikh Manish , Green Philip , Finn Matthew , Garcia Santiago , Doing Anthony , Patel Mitul , Bahadorani John , Tarar Muhammad Nauman J , Thompson Craig A , Banerjee Subhash , Brilakis Emmanouil S
Published: April 2024

Background:
High contrast utilization during chronic total occlusion (CTO) percutaneous coronary intervention (PCI) may lead to peri-procedural complications, in particular contrast-induced nephropathy (CIN).

Methods:
We examined the association between several clinical and angiographic variables and contrast volume utilization during CTO PCI among 950 consecutive procedures performed at 10 experienced US centers between May 2012 and March 2015.

Results:
Mean age was 65±10 years, 87% of patients were men, and 34% had prior coronary artery bypass graft surgery (CABG). Technical and procedural success was 91% and 90%, respectively. The median contrast volume utilization was 260 (IQR:195, 360) mL. Approximately 33% of patients received >310mL of contrast (high contrast utilization). On univariable analysis male gender (p=0.017), moderate or severe calcification (p=0.002) and tortuosity (p=0.004), proximal cap ambiguity (p=0.002), distal cap at a bifurcation (p=0.001), side branch at proximal cap (p=0.02), blunt/no stump (p=0.003), occlusion length (p<0.0001), high J-CTO score (p=0.012), guide catheter size (>7F) (p<0.0001), retrograde approach (p=0.006), ad-hoc CTO PCI (p<0.0001) and dual arterial access (p<0.0001) were associated with higher contrast administration, whereas history of diabetes mellitus (p=0.008) and in-stent restenosis (p=0.049) were associated with less contrast use. On multivariable analysis proximal cap ambiguity (p=0.030), bigger guide catheter size (p=0.007), ad-hoc CTO PCI (p<0.0001) and dual arterial access (p=0.002) were independently associated with higher contrast use during CTO PCI. On the other hand, in-stent restenosis (p=0.027) and presence of interventional collaterals (p<0.0001) were associated with lower contrast use.

Conclusions:
Approximately 1 in 3 patients undergoing CTO PCI receive high contrast volume (>310 mL). Several baseline clinical and angiographic characteristics can help predict the likelihood of high contrast volume administration. This knowledge could be used pre-procedurally and intra-procedurally to guide and intensify efforts to reduce contrast utilization and reduce the risk of contrast-induced complications during CTO PCI.
Abstract 15053: Hypoxic Preconditioning Improves the Effectiveness of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair in Cynomolgus Monkeys With Myocardial Infarction
Authors: Hu Xin Yang , Xu Yinchuan , Wu Yan , Zhao Jing , Zhong Zhiwei , Chen Lihong , Jin Jing , Wu Rongrong , Li Qingju , Wang Yingchao , Cheng Haifeng , Kong Minjian , Zhang Fengjiang , Chen Qi , Wang Chen , Zhan Hongwei , Fan Youqi , Yu Lei , Yang Qian , Sun Jianzhong , Li Qian , Liang Jie , Zhu Wei , Chen Jinghai , Yu Hong , Zhang Jianyi , Wang Jian’an
Published: April 2024

Background:
Experiments in rodents have shown that hypoxic preconditioning (HP) can increase the therapeutic effectiveness of transplanted bone-marrow mesenchymal stem cells (MSCs) for myocardial infarction (MI). Here, we investigated whether the benefits associated with HP-MSC transplantation are also observed in non-human primates with MI.

Methods:
Allogeneic MSCs engineered to express GFP via lentiviral transfection were cultured in 21% oxygen (N-MSCs) or in 0.5% oxygen (HP-MSCs) for 24 hours. MI was surgically induced in Cynomolgus monkeys by ligating the left anterior-descending coronary artery distal to the first diagonal branch. 30 minutes later, 28 monkeys were each treated with 10 million MSCs intramyocardially injection. (N-MSCs: 13 monkeys; HP-MSCs: 15 monkeys). 11 additional monkeys treated with saline were served as control. LVEF and infarct sizes (IS) were measured echocardiographically, and the change in each parameter (ΔLVEF, ΔIS) was calculated by subtracting measurements taken 3 days post MI from measurements taken 28 days post MI. Incidents of ventricular arrhythmia were continuously detected via telemetry. Vascularity, arteriole density, proliferation, and endogenous progenitor-cell activation were evaluated via immunofluorescent assessments of CD31, SMA, Ki67, and c-kit expression, respectively; Engraftment was evaluated via RT-PCR measurements of GFP expression. Apoptosis was assessed with TUNEL staining, and the expression of pro-survival and/or pro-angiogenic genes was evaluated via immunoblot.

Results:
HP increased the expression of several pro-survival/pro-angiogenic factors (Ang 1, EPO, HGF, PDGF-BB) in cultured MSCs, and treatment with HP-MSCs, but not with N-MSCs was associated with significant improvements in ΔLVEF, ΔIS, vascularity, proliferation, and apoptosis. Vascularity and proliferation were also greater in HP-MSC animals than in N-MSC animals, and HP improved measurements of cell engraftment at Day 3, but not at Day 28. The incidence of arrhythmia (PVCs or NSVT) in all three experimental groups was similar.

Conclusions:
HP improved the effectiveness of MSC transplantation for the treatment of MI in non-human primates without increasing the occurrence of arrhythmogenic complications.
Abstract 15186: Simple Sarcopenia Screening Test is Useful to Predict Future Adverse Events in Male Patients With Cardiovascular Risk
Authors: Onoue Yoshiro , Izumiya Yasuhiro , Hanatani Shinsuke , Tanaka Tomoko , Yamamura Satoru , Kumura Yuichi , Araki Satoshi , Ogawa Hisao
Published: April 2024

Introduction:
Progressive loss of skeletal muscle termed “sarcopenia” is an independent risk factor for mortality in patients with cardiovascular diseases. Recently, a simple screening test that can identify sarcopenia using three variables (age, grip strength and calf circumference) has been developed. We utilized the screening test and assessed its clinical utility in patients with cardiovascular risk.

Hypothesis:
Simple sarcopenia screening test predicts future adverse events in patients with cardiovascular risk.

Methods and Results:
The study included 479 patients who have one or more risk factors. The sarcopenia screening score was calculated, and the patients were divided into sarcopenia (n=260) and non-sarcopenia (n=219) group. The sarcopenia group had significantly higher BNP, E/e’, and lower estimated glomerular filtration rate (eGFR) than the non-sarcopenia group. Multivariate linear regression analyses showed that the sarcopenia score correlated significantly with BNP independent of age, sex, hypertension, diabetes mellitus, and eGFR. In multivariate Cox proportional hazards analysis, BNP (ln[BNP]) (hazard ratio [HR]: 2.17; 95% confidence interval [CI]: 1.42-3.32, p<0.01), body mass index (HR: 1.23; 95%CI: 1.05-1.45; p=0.01), NYHA functional classification (HR: 2.84; 95%CI: 1.63-4.95, p<0.01) and the presence of sarcopenia (HR: 2.88; 95%CI: 1.06-7.82; p=0.04) were independent predictors of heart failure re-hospitalization. With regard to the gender difference, Kaplan-Meier curve revealed that event free survival rate was significantly lower only in the male, but not female sarcopenia group. In addition, serum brain-derived neurotrophic factor, known as a brain and skeletal muscle-derived protein, were significantly lower in the male sarcopenia group than non-sarcopenia group.

Conclusions:
Simple sarcopenia screening test could predict the future adverse events in male patients with cardiovascular risk.
Abstract 15275: Altered Extracellular Matrix Proteoglycan- Decorin, Collagens and Elastin Deposition May Enhance Atherosclerosis in Human Peripheral Artery Disease: Implication of Morphological Predictors in Restenotic Plaque Progression
Authors: Krishnan Prakash , K-Raman Purushothaman , Purushothaman Meerarani , Kovacic Jason C , Baber Usman , Tarricone Arthur , Vasquez Miguel , Wiley Jose , Kini Annapoorna , Sharma Samin K , Fuster Valentin , Moreno Pedro R
Published: April 2024

Introduction:
In coronary artery restenosis, reduced proteoglycan-decorin deposition in extracellular matrix (ECM) was shown to be associated with alterations in the types of collagens in ECM. However, in Peripheral Artery Disease (PAD) restenosis, these ECM changes have not been carefully characterized. Alterations in proteoglycan-decorin expression in the ECM may change the fibrillar architecture of collagens, and may alter the type of collagen deposition. HYPOTHESIS: We hypothesize that in PAD restenotic plaques, decreased deposition of proteoglycan-decorin is associated with increased type III collagen and elastin with decreased type I collagen content when compared to de novo control plaques.

Methods:
Thirteen restenotic and thirteen de novo superficial femoral artery plaques were obtained in-vivo during peripheral artery interventional procedure and compared histopathologically for ECM changes. Protein expression profiles of decorin, type I and type III collagen, and elastin deposition were evaluated and graded by immunohistochemistry. H& E stain was used to characterize the plaque morphology and stellate cell grade by scoring.

Results:
(See figure and table). In restenotic atheroma decorin, and type I collagen were decreased (p= 0.0001 for all comparisons). Type III collagen and elastin content were increased (p= 0.0001 for all comparisons) compared to de novo plaques.

Conclusions:
In PAD restenosis, we observed a reduction in decorin with an increase in type III collagen and simultaneous decrease in type I collagen as reported in CAD restenosis. Reparative injurious processes may underlie the associated observation in reduced proteoglycan-decorin in the ECM and altered types of collagen content. Additional molecular biological studies will address the mechanistic mediators which cause these ECM compositional changes.
Abstract 15301: Sustained Presence of Left Ventricular Hypertrophy is Accompanied by Increased Cardiovascular Morbidity in Essential Hypertensives
Authors: Tsiachris D. , Tsioufis C. , Antonakis V. , Dimitriadis K. , Flessas D. , Lagiou F. , Galanakos S. , Milkas A. , Roussos D. , Tousoulis D.
Published: April 2024

Hypothesis:
To investigate the prognostic role of left ventricular hypertrophy (LVH) regression regarding incidence of cardiovascular diseasein essential hypertension.

Methods:
We prospectively followed up for a median period of 3.8 years 1226 essential hypertensives (mean age 57.8 years, baseline office BP=143.6/89.3mmHg). All subjects visited periodically the outpatient hypertensive unit of our institution and office BP at follow up was calculated based on the measurements of the last 3 visits. Echocardiographic evaluation and determination of the metabolic profile and creatinine levels was performed at entry and at follow up. LVH was defined as LV mass index ≥116g/m2 in men and LV mass index ≥96g/m2 in women. Endpoint of interest was the incidence of stroke, coronary artery disease and their composite.

Results:
At the end of follow up the incidence of the composite end-point was 4.0% (17 patients with stroke, 34 with CAD, 2 with both). According to the presence of LVH at baseline (20.2%) and at the end of follow-up (15.9%) patients were divided in two groups: with normal LV mass index at both examinations or with LVH at baseline and regression of hypertrophy (n=1031, 84.1%, group 1) and with LVH at baseline and at follow-up and with normal LV mass index at baseline and LVH at follow-up (n = 195, group 2). Hypertensives of group 2 compared to those of group 1 were older (by 6.3 years, p<0.001), more frequently females (by 19%, p<0.001) and had at baseline greater duration of hypertension (by 2.6 years, p<0.001), increased number of antihypertensive drugs (by 0.6, p<0.001) office pulse pressure levels (by 5mmHg, p<0.001), increased body mass index (by 0.8kg/m2, p=0.024), glucose (by 7.4 mg/dl, p<0.001) and decreased creatinine clearance (by 10.5 ml/min/, p<0.001).Survival analysis revealed that hypertensives without LVH regression (group 2) compared to those of group 1 exhibited significantly higher rates of stroke (5.1% vs. 0.7%, log rank p<0.001) and the composite end-point (7.7% vs. 3.3%, log rank p=0.020).

Conclusions:
Lack of regression of LVH is accompanied by increased incidence of stroke and combined cardiovascular disease in essential hypertensives.
Abstract 15332: Impact of Coronary Lesion Characteristics Assessed by Multidetector Coronary Computed Tomography on Periprocedural Myocardial Necrosis for Chronic Total Occlusion: Multicenter Registry Study
Authors: Usui Eisuke , Niida Takayuki , Araki Makoto , Matsuda Junji , Kanaji Yoshihisa , Murai Tadashi , Lee Tetsumin , Kimura Shigeki , Yonetsu Taishi , Kakuta Tsunekazu
Published: April 2024

Background:
Periprocedural myocardial infarction (PMI) has been shown to be associated with worse prognosis of patients who underwent percutaneous coronary intervention (PCI). Specific characteristics of culprit lesions detected on multidetector computed tomography (MDCT) have not been fully elucidated as predictors of PMI in patients with chronic total occlusion (CTO) lesions. We investigated to determine whether predictive MDCT characteristics exist for PMI associated with CTO PCI.

Methods:
79 stable angina patients with 80 CTO lesions who underwent pre-PCI MDCT and CTO PCI at three institutions between Dec 2011 and May 2015 were included. Lesions were divided into 2 groups based on the presence (PMI group, n=20; 25%) or absence (non-PMI group, n=60; 75%) of post-PCI peak cardiac troponin (cTn) elevation of more than institutional URLx20. Clinical characteristics, procedural variables, and MDCT findings were compared between these two groups. Uni- and multivariate logistic regression analysis were performed to identify the predictors of PMI.

Results:
There was no significant difference in clinical characteristics between both groups. PCI success was achieved in 64 (80%) patients. Fluoroscopic time and contrast use was significantly greater in PMI group. There was no significant difference in the frequency of PMI between PCI success and failure. Frequency of the use of retrograde approach was significantly higher with PMI. In MDCT analysis, lesion length was significantly longer in PMI group (median 35.6 [IQR 26.5-45.8] mm vs. 23.7 [12.8-36.4] mm, p=0.01). Napkin-ring sign (CT density <130HU) was also significantly associated with PMI group (25.0% vs. 6.7%, p=0.04). Multivariate logistic regression analysis revealed that retrograde approach (odds ratio: 6.41; 95% confidence interval: 1.95 to 21.1; p<0.01) was a significant predictor of PMI after controlling for confounding factors. Napkin-ring sign showed a borderline significant association with PMI (odds ratio: 4.64; 95% confidence interval: 0.98 to 22.0; p=0.05).

Conclusion:
PMI is not uncommon in patients undergoing elective CTO PCI regardless of procedure success or failure. MDCT before PCI may help identify patients at high risk for PMI associated with CTO PCI.
Abstract 15393: Cholesterol Esterifying Enzyme Acat2 - A Target for Cardiometabolic Diseases
Authors: Pramfalk Camilla , Ahmed Osman , Larsson Lilian , Karpe Fredrik , Neville Matthew J , Eriksson Mats , Parini Paolo
Published: April 2024

Introduction and Hypothesis:
The cholesterol esterifying enzyme acyl-Coenzyme A: cholesterol acyltransferase 2 (ACAT2, encoded by Soat2) is exclusively expressed in enterocytes and hepatocytes. Soat2-/- mice do not develop atherosclerosis or diet-induced hypercholesterolemia, and accumulate less triglycerides and cholesteryl esters in the liver (hepatic steatosis) when fed a high fat-cholesterol diet. Hepatocyte nuclear factor 1α and 4α play important roles in lipid and carbohydrate metabolism and function as positive regulators of the human SOAT2 gene. This together with the association between hepatic steatosis and insulin resistance, prompted us: 1) to investigate the role of ACAT2 in hepatic steatosis and a potential association between ACAT2 and insulin sensitivity, 2) to assess the effects of different dietary regimens, and 3) to study potential sex-related differences.

Methods:
Wild type and Soat2-/- mice were either fed a high-fat (but low in cholesterol), a high-carbohydrate, or a chow diet. Serum, liver, adipose and muscle tissues were analyzed. Oral glucose and insulin tolerance tests were performed. Plasma from humans bearing a rare exonic variant was analyzed.

Results:
Soat2-/- mice fed a high-fat diet for eight weeks develop less hepatic steatosis, were more insulin sensitive, had lower hepatic expression of glucose transporter 2 and fat specific protein 27 (FSP27, named Cidec in humans). Similar findings were present in Soat2-/- mice fed a high-carbohydrate diet for two weeks. Carrier of a rare exonic variant in CIDEC (rs140125102, Pro73Thr) had lower insulin and HOMA-IR compared to non-carriers.

Conclusions:
Genetic depletion of ACAT2 dramatically reduces hepatic steatosis and improves insulin sensitivity via downregulation of hepatic FSP27/Cidec expression independently of sex and diets. Inhibition of ACAT2 may thus be a strategy to treat cardiometabolic diseases.
Abstract 15410: ACE Gene Dosage Influences the Magnitude of Blood Pressure Increase After Chronic High Fructose Intake: Role of Resistance Arteries
Authors: Moraes-Silva Ivana C , de Souza Leandro E , Irigoyen Maria Claudia , Casarini Dulce E
Published: April 2024

We investigated the mechanisms involved in blood pressure (BP) increase induced by chronic high fructose (F) intake and its association with angiotensin converting enzyme (ACE) dosage.

Male mice harbouring 1, 2 or 3 copies of the ACE gene received F (100g/l) or tap water (C) for 8 weeks. Glucose tolerance and BP were evaluated. BP variability was analyzed in frequency domain. Mesenteric resistance artery reactivity to noradrenaline (Nor; 0.1nM - 1μM), and acetylcholine (Ach; 1nM - 10μM, after or not L-NAME incubation, 100 μM) were studied in an isometric myograph (DMT, 620M).

Glucose intolerance was seen in all F groups vs. C (1 copy: 100+3 vs. F=198+5; 2 copies: 121+4 vs. F=201+8; 3 copies: 86+4 vs. F=212+5 mg/dl at the 120thmin after 1.5 g/Kg ip glucose overload). Systolic BP increased in all F-fed mice (mean C=112+2; F:1 copy=119+3, 2 copies=123+2, 3 copies=129+2 mmHg), with a significant augment in 3-copy group vs. 1 and 2-copy mice. Not only BP variability (1 copy: 39+3 vs. F=57+2; 2 copies: 38+2 vs. F=59+3; 3 copies: 40+3 vs. F=73+7 mmHg
2
) but also its sympathetic component (LF; 1 copy: 5+1 vs. F=12+3; 2 copies: 6+2 vs. F=19+3; 3 copies: 7+2 vs. F=31+5 %) increased in all F groups, with a more pronounced augment in 3-copy mice vs. 1 and 2. Moreover, F-fed 3-copy mice reactivity to Nor was superior than the other groups (1 copy: 170+5; 2 copies: 190+7; 3 copies: 214+10 %) while Ach-induced relaxation was more reduced in 3-copy mice than 1 and 2 (mean C: 76+5%; F: 1 copy=58+8, 2 copies=47+6, 3 copies=36+5 %). L-NAME in F-fed groups significantly blocked ~95% of Ach relaxation in 3-copy mice vs. 75 and 82% in 1 and 2-copy mice, respectively. Additionally, BP variability was negatively correlated to Ach maximal relaxation (r
2
=0.75) and positively correlated to Nor maximal constriction (r
2
=0.78) while glucose levels in the tolerance test were also negatively correlated to Ach maximal relaxation (r
2
=0.72) and positively correlated to Nor maximal constriction (r
2
=0.9).

In conclusion, F-induced BP increase is influenced by ACE levels in mice. Increased BP variability and glucose intolerance are highly associated with microvascular dysfunction.