bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13214: Right Ventricular-Vascular Coupling in Acute Hemodynamic Stress: A Simple Method of Estimation and Relationship With Right Ventricular Ejection Fraction and Afterload
Authors: Mehmood Muddassir , Biederman Robert W , McCarthy Mary C , Tchorz Kathryn M
Published: April 2024

Objectives:
Gold standard of right ventricular (RV) function is ratio of end-systolic to arterial elastance from synchronized volume and pressure measurements. Quantification of ventricular-vascular coupling (VVc) using non-simultaneous common right heart catheterization and cardiac imaging has been described.

Hypothesis:
VVc estimated from simultaneous pressure and volume measurements using Swan-Ganz
TM
(Edwards Lifesciences, Irvine, CA) advanced technology catheters would be feasible and clinically relevant.

Methods:
32 mechanically ventilated adult critically ill trauma/general surgery patients were enrolled within 6 hours of admission. Hemodynamics were transduced every 12 hours for 48 hours. VVc was quantified as ratio of pulmonary artery (PA) effective elastance (E
a
) to RV maximal end-systolic elastance (E
max
). Mean PA pressure (mPAP) was used as surrogate of RV end-systolic pressure. Right ventricular end-systolic volume index (ESVI) was calculated as difference of end-diastolic volume index and stroke volume index (SVI). E(a) was calculated as (mPAP - PCWP)/SVI and E(max) as mPAP/ESVI.

Results:
Serial E
a
/E
max
inversely correlated with RV ejection fraction (RVEF) (r = -0.89, p <0.001; r = -0.57, p = 0.001; r = -0.73, p <0.001; r = -0.38, p =0.052, and r -0.55, p <0.03) (Figure 1) and pulmonary arterial capacitance (PAC) (r = -0.59, -0.64, -0.49, -0.53, and -0.41, p ≤ 0.03). Pulmonary vascular resistance (PVR) correlated with E
a
/E
max
(r = 0.66, 0.61, 0.68, 0.66, 0.52, p ≤ 0.004). Non-survivors (n = 7) had higher E
a
/E
max
(indicating uncoupling) at 48 hours (2.3 ± 1.8 vs. 1.4 ± 1.8, p = 0.036). AUC for Ea/Emax at 48 hours and mortality was comparable to RVEF.

Conclusions:
In mechanically ventilated critically ill and/or injured adults, estimation of VVc using advanced technology pulmonary artery catheter is feasible. E
a
/E
max
is related to PVR and inversely related to RVEF and PAC. Estimation of E
a
/E
max
may assist in optimization of resuscitation.
Abstract 13273: Long-term Administration of Eicosapentaenoic Acid Prevents an Excessive Blood Pressure Elevation During Exercise Simulating Ordinary Activities of Daily Living via the Improvement of Vascular Endothelial Dysfunction in Patients With Hypertension
Authors: Aoyama Akihiro , Masuda Takashi , Ogura Misao , Akiyama Ayako , Kamada Yumi , Tanaka Shinya , Kamiya Kentaro , Hamazaki Nobuaki , Matsuzawa Ryota , Nozaki Kohei , Nakamura Takeshi , Yabu Kanae , Maekawa Emi , Ako Junya
Published: April 2024

[Background]
Excessive blood pressure (BP) elevation was frequently observed during exercise even at low or moderate intensity in patients with hypertension (HT), although their BP at rest was successfully controlled with antihypertensives. Several studies documented that vascular endothelial dysfunction induced excessive BP elevation in their ordinary activities of daily living (ADL). On the other hands, eicosapentaenoic acid (EPA) reduces oxidative stress and vascular inflammation resulting in the improvement of vascular endothelial dysfunction. However, it is still unknown whether long-term administration of EPA ameliorates excessive BP elevation in ordinary ADL. This study aimed to investigate the influence of EPA on vascular endothelial dysfunction and excessive BP elevation during exercise at moderate intensity in HT patients.

[Methods]
We recruited 60 HT outpatients whose resting blood pressure was successfully controlled below 140/90 mmHg. Patients were assigned to EPA(+) group or EPA(-) group in crossover method. They were administered antihypertensives with or without 1,800 mg of EPA daily for 10 months in the EPA(+) and EPA(-) groups, respectively. We measured serum concentrations of EPA, arachidonic acid (AA) and EPA/AA ratio. We assessed reactive hyperemia index (RHI) and thrombomodulin (TM) as a parameter of vascular endothelial function. BP elevation during exercise was determined as the difference from systolic BP (SBP) at rest to peak SBP during a cycle ergometer exercise test (SBP). The exercise intensity was given as 75% of peak heart rate (HR) obtained from a treadmill exercise test, which indicates the intensity of ordinary ADL. We compared all parameters between the two groups and analyzed the relationship between RHI and SBP.

[Results]
EPA, EPA/AA ratio and RHI were significantly higher in the EPA(+) group than in the EPA(-) group (P<0.01, respectively). SBP and TM were significantly lower in the EPA(+) group than in the EPA(-) group (P<0.05, respectively). RHI was negatively correlated with SBP (r=-0.313, P<0.05).

[Conclusion]
Long-term administration of EPA prevented an excessive BP elevation during exercise simulating ordinary ADL via the improvement of vascular endothelial dysfunction in HT patients.
Abstract 13304: Thrombin-activated Fibrinolysis Inhibitor in Chronic Thromboembolic Pulmonary Hypertension
Authors: Yaoita Nobuhiro , Satoh Kimio , Satoh Taijyu , Sugimura Koichiro , Tatebe Shunsuke , Yamamoto Saori , Aoki Tatsuo , Miura Masanobu , Shimokawa Hiroaki
Published: April 2024

Introduction:
The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) remains to be elucidated. In the present study, we examined whether fibrinolysis capacity is impaired in CTEPH patients with a special reference to thrombin-activated fibrinolysis inhibitor (TAFI) and if so, whether TAFI is also directly involved in the pathogenesis of CTEPH in mice and humans.

Methods and Results:
We enrolled 68 consecutive patients undergoing right heart catheterization in our hospital, including those with CTEPH (n=27), those with pulmonary arterial hypertension (PAH, n=22) and controls (non-PH, n=19). Whole blood clot-lysis assay with monteplase (100 ng/ml) showed that thrombus reduction rate was significantly reduced in CTEPH compared with PAH or controls (58.1 vs. 73.5 and 75.1%, both P<0.01). Plasma clot-lysis assay showed that the clot lysis time tended to be prolonged in CTEPH compared with PAH or controls (894 vs. 652 and 720 sec, both P=0.07). Moreover, serum levels of TAFI were significantly higher in CTEPH than in PAH or controls (46.1 vs. 39.1 and 38.7 μg/ml, both P<0.05), which remained unchanged even after hemodynamic improvement by percutaneous transluminal pulmonary angioplasty (49.6 vs. 50.0 μg/ml, P=0.92). The levels of TAFI released from the platelets upon stimulation by thrombin (0.05 U/ml) were significantly higher in CTEPH than in PAH or non-PH (2.7 vs. 1.7 and 1.0 folds, both P<0.05). Additionally, thrombus reduction rate was significantly improved with a carboxypeptidase R (an inhibitor of activated TAFI) (62.0 vs. 73.4%, P<0.01) or prostaglandin E1 (an inhibitor of activation of platelets) (62.2 vs. 70.4%, P<0.01). Importantly, plasma levels of TAFI were correlated with thrombus reduction rate and improved thrombus reduction rate by an activated TAFI-inhibitor (both P<0.05). Finally, we newly developed TAFI-overexpressing mice (TAFI-Tg) and found that intravenous injection of thrombin (100 units/kg) caused accelerated thrombotic obstruction of the pulmonary artery in TAFI-Tg mice compared with littermate controls (5.4±1.2 vs. 1.8±0.6 vessels/lung fields) (n=9, P<0.05).

Conclusions:
These results provide the first evidence that TAFI plays a crucial role in the pathogenesis of CTEPH.
Abstract 13343: Green Tea Polyphenol Attenuates Experimental Abdominal Aortic Aneurysm Progression in a Rat Model
Authors: Setozaki Shuji , Minakata Kenji , Hirao Shingo , Ikeda Tadashi , Sakata Ryuzo
Published: April 2024

Introduction:
Destruction of elastin in the media layer is thought to play an important role in the development of abdominal aortic aneurysm (AAA). It has been reported that a major component of green tea, epigallocatechin-3-gallate (EGCG), enhances the stabilization of elastin and facilitates the regeneration of elastin in vitro. However, it is unknown whether EGCG attenuates AAA development in vivo.

Hypothesis:
We aimed to prove the hypothesis that administration of EGCG can attenuate AAA development.

Methods:
We divided 48 male SD rats into two groups: the control group (n=24) and the EGCG group (n=24). A 1.0 mmol/L EGCG solution was administered orally for 2 weeks prior to the induction of AAAs in the EGCG group until sacrifice, while tap water was given to the control group. AAAs were induced by administration of intraluminal elastase and extraluminal calcium chloride. Immediately before the induction of the AAAs (on day 0) and on day 7 after their induction, 6 rats were sacrificed in each group. In addition, 12 rats were sacrificed in each group on day 28. The aortic size was measured and aortic tissues underwent biochemical and histological evaluation.

Results:
The abdominal aortic size on day 28 was significantly smaller in the EGCG group than in the control group (2.34 ± 0.12 vs 2.86 ± 0.19mm, p<.0001). The thickness of the media layer increased significantly in the EGCG group compared with that of the control group (68.4 ± 13.6 vs 46.9 ± 13.6μm, p<0.001). The elastin content of the media layer was significantly greater in the EGCG group than in the control group (20.3 ± 4.8 vs 9.6 ± 3.7%, p<.0001). The lysyl oxidase (LOX) mRNA level in the aortic tissues on day 0 was significantly higher in the EGCG group than in the control group (p<0.05). Transmission electron microscopy images showed the growth of new elastic fibers in the EGCG group. On immunohistochemical staining, the LOX-positive area was significantly larger in the EGCG group than in the control group (p<0.01).

Conclusions:
Oral treatment with EGCG attenuated AAA progression in a rat model via organization and stabilization of elastin in the media layer by increasing LOX production. Thus, the green tea polyphenol EGCG has the potential to serve as a pharmacological agent to treat and prevent AAAs.
Abstract 13360: Impact of Aortic Valve Calcification on the Incidence of Periprocedual Myocardial Injury in Patients Undergoing Coronary Stent Implantation
Authors: Shibata Yohei , Suzuki Susumu , Ishii Hideki , Harada Kazuhiro , Hirayama Kenshi , Tatami Yousuke , Ota Tomoyuki , Murohara Toyoaki
Published: April 2024

Object:
Previous studies have shown an association between aortic valve calcification (AVC) and cardiovascular events and mortality. On the other hand, periprocedual myocardial injury (PMI) is known as a predictor of subsequent mortality and other poor clinical outcomes.

Hypohtesis:
We assessed the hypothesis that presence of AVC could predict PMI in elective percutaneous coronary intervention (PCI).

Methods:
This study included a total of 372 patients treated with PCI for stable angina pectoris. Aortic valve calcification was defined as bright echoes >1mm on one or more cusps of aortic valve by ultrasound cardiography. PMI was defined as an increase in high-sensitivity troponin T >5 times (0.070 ng/ml) the upper normal limit at 24hours after PCI.

Results:
AVC was detected in 46.0% (n = 171). The incidence of PMI was significantly higher in patients with AVC than in those without AVC (43.9% vs 10.9%, respectively, p < 0.001). The presence of AVC independently predicted PMI after adjusting for other significant variables (OR 2.18, 95% CI 1.30 to 3.66, p = 0.003). Other predictors were estimated glomerular filtration rate (OR 0.975, 95% CI 0.962 to 0.989, p < 0.001), left anterior descending artery lesion (OR 0.496, 95% CI 0.293 to 0.840, p = 0.01) and total stent length (odds ratio 1.02, 95% confidence interval 1.00 to 1.05, p = 0.03).

Conclusion:
In conclusion, presence of AVC could predict incidence of PMI. Because detection of AVC by ultrasound cardiography is very simple, it is useful for risk stratifications in elective PCI with stent implantation.
Abstract 13381: The Association of Aortic Valve Weight With Echocardiographic Indices of Aortic Stenosis Severity in 610 Patients With Normal Left Ventricular Ejection Fraction Undergoing Surgical Aortic Valve Replacement for Severe Isolated Aortic Stenosis
Authors: Alexandru Dragos , Petillo Florentina , Pollack Simcha , Reichek Nathaniel , Barasch Eddy
Published: April 2024

Background:
The magnitude of aortic valve calcification (AVC) is associated with aortic stenosis (AS) severity. AV weight (AVW)is an accurate measure of valvular calcium load, and reportedly, correlates more closely with transvalvular pressure gradients than with AV area (AVA). Hypothesis: Due to multiple assumptions made when measuring or calculating the echocardiographic (echo) variables used for determination of AS severity, their association with AVW is only modest.

Methods:
Between 2010-14, 610 consecutive patients (pts) undergoing surgical AV replacement (AVR) for severe isolated AS,(age 76.4 ± 9.3 yrs, 58% men, AVA index 0.36 ± 0.09 cm2 /m2, EF = 61.0 ± 5.0 %), had AVs weighed (mean AVW = 2.5 ± 1.1 g, median = 2 gs, range: 1-11 g), and preoperative echo studies. Pearson correlation was used to measure the linear association between AVW and the echo variables, and a number of covariates (specified in the table) were included through the calculation of partial correlation.

Results:
Women have a lower AVW than men by 0.6 g (24%) (p<0.0001) when normalized for BSA (p<0.0001) or AVA index (p<0.0001) but not when corrected for aortic annular area. Compared with pts with low gradients, those pts with MG ≥ 40 mm Hg had 0.4 g (17%) higher AVW (p<0.0001) whereas no difference were found between those with normal vs low stroke volume index. Bicuspid AV are heavier than tricuspid valves (3.3 ± 2 gr vs. 2.4 ± 0.9 g, p = 0.001) even when adjusted for BSA, AVA and annular area. The correlations of AVW with echo variables are shown below. Conclusions: 1. In severe isolated AS with normal EF, AVW is modestly associated with pressure gradients, and not with LV stroke work loss. 2. Women have lower AVW than men due to smaller aortic annulus, and those with MG≥40 have higher AVW than those with MG<40 as those with bicuspid vs, tricuspid AVs. 3. These findings should be considered when interpreting the non-invasive studies evaluating AV calcium load in challenging cases of severe AS.
Abstract 13392: Clinical Significance of Hematuria in Patients With Atrial Fibrillation Receiving Oral Anticoagulation Therapy
Authors: Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Pak Hui-Nam , Lee Moon-Hyoung , Joung Boyoung
Published: April 2024

Introduction:
The presence of hematuria is frequently related with underlying genitourinary pathologies such as urolithiasis or malignancies. Although hematuria is an important and common complication in atrial fibrillation (AF) patients taking oral anticoagulation therapy (OAT), its clinical implication is not fully elucidated.

Objectives:
We evaluated the clinical significance of hematuria and its relationship with genitourinary disease in patients with AF.

Methods:
This study included 18,086 consecutive AF patients with (OAT+, n=11,432) or without OAT (OAT-, n=6,654) who visited to a tertiary Hospital from January 2005 to April 2015. The degree of urinary red blood cells (RBC) was reported to range from 0 to 3+ on random urinalyses. The incidence of cancer or stone in the genitourinary tract (kidney, ureter, and bladder) was evaluated. All data were obtained from the Clinical Data Repository System.

Results:
Overall, 144 (0.8%) patients had malignancies and 164 (0.9%) patients had stones in the genitourinary tract. Hematuria was observed in 3,737 (32.7%) and 2,017 (30.3%) in patients with and without OAT (p=0.001), and the large (≥ urine RBC 3+) hematuria was observed in 1,382 (12.1%) and 666 (10.0%) patients with and without OAT, respectively (p<0.001). While 39 (2.8%) OAT+ patient with large hematuria had malignancies, 8 (1.2%) OAT- patient had (p=0.026). However, if the patients had small hematuria (urine RBC 1+ or 2+), the incidence of genitourinary cancer was not different between OAT+ and OAT- groups (p=0.266). The incidence of genitourinary tract stone in patients with large or small hematuria was comparable between OAT+ and OAT- groups.

Conclusions:
Large hematuria was associated with higher incidence of cancer in the genitourinary tract in OAT+ group, but not in OAT- group. A meticulous evaluation of the cause of hematuria is needed, if AF patients receiving OAT had large hematuria.
Abstract 13459: Usefulness of B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin for Risk Stratification in Low Flow, Low Gradient Aortic Stenosis -A Substudy of the TOPAS Study
Authors: Dahou Abdellaziz , Clavel Marie-Annick , Capoulade Romain , Dumesnil Jean G , Pibarot Philippe
Published: April 2024

Background:
B-type natriuretic peptide (BNP) and troponin T (TNT) have been shown to be associated with outcome in several clinical conditions. However the prognostic value of these 2 biomarkers combined together remains unclear. We aimed to explore the prognostic value of combined BNP and high-sensitivity TNT (hsTNT) in patients with low flow low gradient aortic stenosis (LGLG AS).

Methods:
Ninety eight patients (74±10 year; 75% men) with LFLG AS (LVEF <50% and/or SVi<35 ml/m2, mean gradient<40 mmHg, AVAi<0.6 cm2/m2) were prospectively enrolled in the TOPAS study and included in this analysis. The cohort was divided into three groups according to BNP and hsTNT plasma levels: Group A, patients with BNP<550 pg/mL and undetectable TNT (hsTNT<0.015 ng/mL); Group B, with BNP≥550 pg/mL or hsTNT≥0.015 ng/mL and Group C, patients with BNP≥550 pg/mL and hsTNT≥0.015 ng/mL. The primary endpoint was all-cause mortality.

Results:
Among the 98 patients, 32 (33%) were in Group A, 39 (40%) in Group B and 24 (27%) in Group C. During a median follow up of 2.8 [IQR=1.1-4.1] years, 55 patients died. Patients in Group C were older and had lower LVEF (all p<0.05). Two-year mortality was higher in Group C (41±9%) than in Group B (23±7) and Group A (5±4%) (p=0.0019). In Group B, there was no significant difference in 2-year mortality rates between the subgroup with hsTNT≥0.015 ng/mL versus that with BNP≥550 pg/mL (26±9% vs. 11±10%, respectively, p=0.21). In multivariable analysis adjusted for age, type of treatment (AVR vs. conservative), coronary artery disease and LVEF, Group C remained independently associated with increased risk of mortality (HR= 4.25; p=0.023), and Group B tended to have higher mortality (HR=3.63; p=0.058) as compared to Group A.

Conclusion:
The results of this study demonstrate the usefulness of combined measures of BNP and hsTNT to enhance risk stratification in patients with LFLG AS. Patients having activation of both BNP and hsTNT have a 4-fold increase risk of mortality.
Abstract 13493: Intracellular Cholesterol Transport Proteins Enhance Hydrolysis of HDL-delivered Cholesteryl Esters and Facilitate Preferential Elimination of Resulting Cholesterol Into Bile as Bile Acids
Authors: Bie Jinghua , Wang Jing , Ghosh Shobha
Published: April 2024

HDL-associated cholesterol, >80% esterified (HDL-CE) entering the hepatocyte via SR-BI can have multiple fates: 1) re-secretion as nascent HDL; 2) re-esterification and either storage of resulting CE or secretion of CE as VLDL; 3) secretion of free cholesterol into bile; and 4) conversion to and secretion of bile acids into bile. While fates 1 and 2 will lead to recirculation of HDL-CE returning to the liver from the periphery including plaque associated macrophage foam cells, fates 3 and 4 will lead to final elimination of cholesterol from the body and would be anti-atherogenic. Although we earlier identified cholesteryl ester hydrolase (CEH) as the hepatic enzyme responsible for the hydrolysis of SR-BI delivered HDL-CE, intracellular factors affecting the directional movement of HDL-derived FC remain undefined. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins (SCP-2 and FABP1) not only facilitate CEH mediated hydrolysis of HDL-CE but also enhance elimination of cholesterol into bile. Primary C57BL/6 mouse hepatocytes were used and expression of CEH, FABP1 or SCP2 was modulated by using respective adenoviruses; AdLacZ was used as control. Over-expression of SCP2 or FABP1 significantly increased hydrolysis of HDL-[
3
H]-CE (A) and reduced the re-secretion of HDL-derived cholesterol as nascent HDL (B). However, over-expression of SCP2 or FABP1 increased the secretion of cholesterol from HDL-[
3
H]-CE as bile acids (C). Flux of HDL-[
3
H]-CE into bile was monitored in vivo using C57BL/6 mice. Similar to the effects seen in vitro, adenovirus-mediated over-expression of FABP1 and SCP2 significantly increased the flux of cholesterol from HDL-[
3
H]-CE to bile acids (D). Taken together, these studies demonstrate that SCP2 and FABP1 facilitate the preferential movement of HDL-associated cholesterol to bile for final elimination from the body. Studies are in progress to establish the anti-atherogenic role of these proteins
Abstract 13521: Novel Protective Role of Cu Transporter ATP7A Against Cardiac Fibrosis by Inhibiting Endothelial-Mesenchymal Transition Mediated Through Snail and Antioxidant-1
Authors: Youn Seock-Won , Varadarajan Sudhahar , Das Archita , Surenkhuu Bayasgalan , Fukai Tohru , Ushio-Fukai Masuko
Published: April 2024

Cardiac fibrosis is attributed to excess pathological deposition of extracellular-matrix (ECM) components; however, it is also mediated through endothelial-mesenchymal transition (EndMT) and fibroblast-myofibroblast transition (FMT) with unknown mechanisms. Copper (Cu), essential micronutrient, has been implicated in fibrosis. Bioavailability of Cu is tightly controlled by Cu-transporter ATP7A which obtains Cu from Cu chaperone Antioxidant-1 (Atox1), and delivers Cu to the ECM secretory Cu enzyme lysysl oxidase (LOX) or exclude Cu. Atox1 also functions as a Cu-dependent transcription factor. However, role of ATP7A in cardiac fibrosis remains unknown. Here we show that high dose angiotensin II infusion (740ng/kg/min for 10 days) to ATP7A mutant (ATP7Amut) mice with reduced Cu transport function significantly increased cardiac fibrosis (200%) and Cu (170%) compared to wild type mice. Blood pressure and heart/body weight were similar between each group. ATP7Amut mice showed increased Isolectin B4+/αSMA+ cells, indicating EndMT in fibrosis region, which was associated with increase in fibrosis-related genes (αSMA, TGFβ1/2/3, CTGF). In ATP7Amut fibroblasts, although LOX activity was reduced, phenotypic conversion to αSMA+ myofibroblasts (FMT) was accelerated. In ECs isolated from ATP7Amut mice or ATP7A-depleted HUVECs, EC phenotype was converted to mesenchymal phenotype with reduced expression of ECs markers (VE-cadherin, VEGFR2) and increased mesenchymal markers (αSMA, TGFβ2) and Cu levels. Functionally, conditioned media from ATP7A-depleted HUVECs promoted cardiac fibroblast differentiation to myofibroblasts (FMT). Mechanistically, ATP7A knockdown in ECs increased expression of EndMT master regulatory transcription factor Snail as well as Atox1 (2 fold). Atox1 overexpression by adenovirus increased EndMT-inducing genes (αSMA, TGFβ2, Hey2) via binding to their promoters at Atox1 binding sites (GAAAGA) without affecting EC markers or Snail which is shown to reduce EC markers. In summary, ATP7A limits cardiac fibrosis by inhibiting EndMT and FMT via suppressing transcription factors Snail and Atox1. Thus, ATP7A is a potential therapeutic target for fibrosis-dependent cardiovascular diseases.
Abstract 13565: Patterns of Newly Detected Atrial Fibrillation and Antithrombotic Treatment in GLORIA-AF Phase II
Authors: Halperin Jonathan L , Huisman Menno V , Diener Hans-Christoph , Dubner Sergio J , Ma Changsheng , Rothman Kenneth J , Schoof Nils , Elsaesser Amelie , Paquette Miney , Bartels Dorothee B , Teutsch Christine , Lip Gregory H
Published: April 2024

Purpose/Background:
Anticoagulation with Vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) is recommended for patients with atrial fibrillation (AF) and additional risk factors for stroke, regardless of the pattern of AF. Using an inception cohort design, GLORIA-AF collected data on antithrombotic therapy choices for patients with newly identified AF at risk of stroke in the course of routine care.

Methods:
Phase II began after the first NOAC became available for stroke prevention in AF and baseline data were recorded from November 2011 through December 2014 in 44 countries worldwide. To reduce selection bias, patients were recruited consecutively, irrespective of antithrombotic therapy received. Antithrombotic treatment is presented in relation to CHA
2
DS
2
VASc scores and the pattern of AF.

Results:
In phase II of GLORIA-AF, 15,092 patients with a recent diagnosis of AF and CHA
2
DS
2
VASc scores ≥ 1 were enrolled. Median age was 71 years and 39.1% were
≥
75 years old; 45.5% were female, 74.6% had a history of hypertension, 23.1% diabetes mellitus and 86.1% had CHA
2
DS
2
VASc scores ≥ 2. AF was classified as paroxysmal in 53.4% (n = 8052), persistent in 35.5% (n = 5362) and permanent in 11.1% (n = 1678) of patients. Relationships of initial antithrombotic therapy to AF pattern and stroke risk are shown in the figure below and further data on regional differences will be presented.

Conclusion:
Initial antithrombotic therapy diverged from guideline recommendations. Patients with paroxysmal AF were less often anticoagulated than those with persistent or permanent AF, and nearly 22% of patients with paroxysmal AF at high stroke risk were untreated, or given aspirin or other antiplatelet therapy alone.
Abstract 13595: Folic Acid Protects Embryo From Environmental Effects on Lipid Metabolism During Cardiac and Placental Development
Authors: Linask Kersti K , Han Mingda
Published: April 2024

Introduction:
Congenital heart defects (CHDs) are the most prevalent of human birth defects with males exhibiting more severe types of CHDs. Cardiac cell and placental trophoblast differentiation are two embryonic processes occurring early between E6.5-E8.0 of mouse gestation (16-19 days of human pregnancy) that can be interfered with by environmental factors to induce anomalies.

Objective:
To determine the predominant pathway(s) targeted by exposures to lithium (Li+), homocysteine (HCys) , or alcohol (ethanol, EtOH) that result in CHDs and that can be protected by high dose folic acid (FA) supplementation.

Method:
On morning of conception, pregnant mice were placed on a protective, high FA diet (10 mg/kg) or on a health maintenance FA diet (3.3 mg/kg) that did not prevent CHDs. At gastrulation (E6.75) the mice received an i.p. injection of Li, HCys, or EtOH. Pregnant control groups received either the protective high FA or the normal FA maintenance diet and an i.p. injection of physiological saline only. Echocardiography on E15.5 determined embryos with abnormal cardiac function. All abnormal hearts and normal control hearts were removed, total RNA extracted. Microarrays were used to evaluate gene changes.

Results:
Significant expression changes among 12 treatment groups with Li and HCys exposures indicated that Gene Ontology (GO) categories involving lipid metabolism were chiefly altered. When the GO sets were sorted according to gender, male embryos displayed greater changes in lipid-related categories than the female. Validation studies demonstrated that Acyl CoA dehydrogenase medium length chain (Acadm) and its protein product important in fatty acid oxidation were modulated by the exposures, including by alcohol. Oil Red O (ORO) localization of neutral lipids in the heart and placenta demonstrated that lipids are highly altered possibly related to altered umbilical blood flow seen with embryos showing abnormal cardiac function. High FA restored normal ORO patterns, placental blood flow, and heart function.

Conclusions:
Li, HCys and alcohol exposed embryos display altered lipid metabolism. Early gestational supplementation with high-dose FA protects lipid metabolism at control levels, maintains placental physiology, and prevents CHDs.
Abstract 13618: Effects of Type 1 Interferon on Blood-derived Smooth Muscle Progenitor Cells Differentiation and Arterial Wall
Authors: Diao Yanpeng , Mohandas Rajesh , Lee Pui , Liu Zhiyu , Sautina Larysa , Mu Wei , Shiyu Li , Wen Xuerong , Croker Byron , Segal Mark
Published: April 2024

Introduction:
System lupus erythematosus (SLE) patients have premature atherosclerosis not explained by traditional risk factors and half have elevated Type-I Interferon (IFN-I) levels.

Hypothesis:
We hypothesized that IFN-I would induce premature atherosclerosis by affecting the differentiation of circulating smooth muscle progenitor cells (SMPC) and promoting atherosclerosis within the vasculature.

Methods:
SMPC isolated from wild-type (WT) and IFN receptor knock-out (IFNR-KO) animals were cultured in medium ± IFN-I and ± TGF-β. In vivo, we analyzed the effect of muscle electroporation of IFN-I cDNA on the number of SMPC and sections of the abdominal aorta bifurcation.

Results:
After 2 weeks culture, IFN-I containing media led to an increase in the number of SMPC isolated from WT animals but no change when the SMPC were isolated from IFNR-KO mice. When the cultured cells were sorted, there was little monocytes/macrophage (CD14, CD36 and F4/80) marker expression while the expression of CD34 increased 50% (Figure), approximately. Real-time PCR revealed that the mRNA of calponin, SM-α-actin and SM22 increased 0.33, 4.5 and 75.1 times, respectively, while SM-myosin heavy chain was unchanged after treatment with IFN-I. Our in vivo results demonstrate a marked increase in pre-atherosclerotic like lesions and significant endothelium damage in WT mice expressing IFN-I for 3 months. However, there was no significant difference in arterial media thickness and cell density between IFN-I treated mice and control. Within these lesions, we observed “immature SMC,” cells that expressed CD34, SM-α-actin, but no SM myosin heavy chain (Figure).

Conclusions:
Our findings suggest that IFN-I enhances SMPC number, and maintains them in an “immature” state while TGF-β might skew SMPC along a non-SMC pathway. These results suggest a role of IFN-I in atherosclerosis by affecting SMPC maturation and have implications for the pathogenesis of atherosclerosis in lupus patients.
Abstract 13646: Electrical Stimulation Upregulates the miR-99 Family to Promote Cardiac Differentiation and Maturation of Human iPS Cells
Authors: Guo Linlin , Liang Jialiang , Huang Wei , Cai Wenfeng , Wang Lei , Wang Jiapeng , Paul Christian , Millard Ronald W. , Xu Meifeng , Wang Yigang
Published: April 2024

Background:
Electrical stimulation (ES) can efficiently promote cardiomyocyte differentiation and maturation of several cardiac progenitors, but the underlying mechanism has not yet been identified. This study aims to determine whether microRNAs (miRs) contribute to ES-induced cardiomyogenesis of human induced pluripotent stem cells (hiPSCs).

Methods and Results:
HiPSCs were induced into cardiomyocytes by our defined ES approaches (a biphasic square pulse (5ms) at 5 Hz frequency and with voltage of 0.5-1.0V/cm), and non-ES as treatment control. Cardiac markers (cTnT, Nkx2-5 and α-MHC) were significantly upregulated in hiPSCs with ES treatment as determined by qPCR (Fig.A), Western Blot, and immunostaining (Fig.B). The profile of miRs responsible for ES-induced cardiomyogenesis was analyzed by microarray and qPCR. Importantly, miR-99 family (Fig.C) (i.e., miR-99a and miR-100) were significantly upregulated in hiPSC-derived cardiac cells with ES treatment. Expression of cardiac genes in differentiated hiPSCs with ES treatment was decreased by miR-99a inhibition. Conversely, miR-99a overexpression enhanced sarcomeric maturation of hiPSC-derived cardiac cells under ES, as observed with immunostaining (Fig.E) and transmission electron microscopy. MiR-99a also enhanced the cardiac electrophysiological maturation as determined by patch clamp and calcium influx measurements. MiR-99a putatively targeted the 3'-UTR of
BMPR2
mRNA (Fig.D) to facilitate cardiac maturation in hiPSCs, as identified by qPCR and the luciferase reporter assay.

Conclusion:
The miR-99 family appears to act as a crucial mediator for cardiogenic maturation of hiPSCs treated with ES. ES can enhance cardiac gene expression and structural maturation of hiPSCs for
in vitro
heart regeneration.
Abstract 13665: Implantable Cardioverter Defibrillator Patients With Chronic Obstructive Pulmonary Disease Are at Higher Risk of Early and Long-Term Mortality
Authors: Shahreyar Muhammad , Mirza Mahek , Shearer Robyn , Choudhuri Indrajit , Nangia Vikram , Mortada M. Eyman , Dhala Anwer , Niazi Imran , Bhatia Atul , Sra Jasbir , Jahangir Arshad
Published: April 2024

Introduction:
Despite chronic obstructive pulmonary disease (COPD) being recognized as a risk factor for mortality in the general population, the impact of COPD diagnosis on early (<1 year) and long-term mortality (>=3 years) in patients at high risk of sudden cardiac death (SCD) with implantable cardioverter defibrillator (ICD) is inadequately studied.

Methods:
Consecutive patients from Jan 2010 to Dec 2013 who underwent an ICD placement were included and differences in overall mortality within 1 year and 3 years after ICD implant between COPD and non-COPD patients were determined using Kaplan-Meier analysis. Predictors of early and late mortality were determined using logistic regression.

Results:
Out of 3,464 patients (mean age 66.5 ± 13.3), 926 (26.7%) patients had a diagnosis of COPD. Overall mortality within 1 year after ICD implantation was 1.62 fold higher in patients with COPD (13% vs 8%: p<0.001) and 1.54 fold higher at 3 years (34% vs 22%: p<0.001) [Figure]. There was no significant age or gender difference between those with and without COPD. Patients with COPD were more likely to have history of myocardial infarction, ischemic cardiomyopathy, heart failure, atrial fibrillation, hypertension, diabetes, hyperlipidemia, obstructive sleep apnea and left ventricle ejection fraction <35%. On logistic regression analysis after correction for these baseline differences, COPD remained an independent predictor of early and late mortality [HR 1.40 (95% CI: 1.22 - 1.61; p-value <0.0001)]. Other independent predictors of mortality were age >65 years, history of heart failure, dialysis, atrial fibrillation and diabetes mellitus.

Conclusions:
COPD is associated with both early and long-term mortality in patients receiving ICD implant for high risk of SCD. Whether a more aggressive management of COPD improves survival in this high-risk population needs to be further assessed for the benefit of this lifesaving but expensive therapy to be maximized.
Abstract 13731: Activation of Focal Adhesion Kinase Leads to the Development and Progression of Abdominal Aortic Aneurysm in Mice
Authors: Harada Takasuke , Yoshimura Koichi , Yamashita Osamu , Ueda Koshiro , Morikage Noriyasu , Hamano Kimikazu
Published: April 2024

Introduction:
Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation, which contributes to the pathological remodeling of extracellular matrix. Focal adhesion kinase (FAK) is involved in the interactions between cells and extracellular matrix, and has been suggested to regulate the remodeling of extracellular matrix.

Hypothesis:
We assessed the hypothesis that FAK plays a pivotal role in the development of AAA.

Methods and Results:
Aortic wall specimens were obtained from patients that underwent aortic surgery (AAA; n=25, non-AAA; n=8). Levels of activated FAK were significantly increased in AAA walls compared with non-AAA walls (2.8 ± 2.3 fold, p<0.05). Activated FAK was localized to macrophages in the outer media and adventitia of AAA walls. We performed a comprehensive analysis of proteins secreted from mouse macrophages in vitro. The FAK inhibitor PF573228 significantly reduced the secretion of monocyte chemoattractant protein-1 and matrix metalloproteinase-9 in macrophages after stimulation with tumor necrosis factor-alpha. Further, we created AAA in C57BL/6 male mice by periaortic application of calcium chloride to investigate the role of FAK activation in vivo. From just after application of calcium chloride, mice were treated daily with PF573228 or vehicle for 6 weeks. Treatment of mice with PF573228 significantly prevented the increase in aortic diameter (PF573228; 0.84 ± 0.08 mm, vehicle; 1.19 ± 0.18 mm, p<0.01). Treatment with PF573228 also reduced inflammatory cell infiltration and disruption of the elastic lamellae. In an additional experiment, PF573228 or vehicle was administered daily from weeks 3 to 6 after application of calcium chloride. Interestingly, delayed treatment with PF573228 significantly inhibited the progression of aneurysmal dilatation (PF573228; 0.88 ± 0.18 mm, vehicle; 1.25 ± 0.27 mm, p<0.05).

Conclusions:
Our results indicate a critical role for FAK activation in the development and progression of AAA in vivo, indicating that FAK represents a novel therapeutic target for preventing and treating AAA.
Abstract 13816: Dantrolene Enhances Binding of Calmodulin to RyR2 in CPVT Which Mutation Located at Central Domain but Does Not Enhance That in CPVT With Mutation at CaM-like Domain
Authors: Nishimura Shigehiko , Yamamoto Takeshi , Fukui Go , Maeda Takako , Hino Akihiro , Suetomi Takeshi , Ono Makoto , Mochizuki Mamoru , Oda Tetsuro , Okuda Shinichi , Kobayashi Shigeki , Yano Masafumi
Published: April 2024

Introduction:
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by heterozygous mutation in RyR2 gene. Most mutations are known to be located at N-terminal domain, central domain or C-terminal channel pore region. Meanwhile, amino acid residues from 4026 to 4172 of RyR2 have EF hand motifs and are called calmodulin (CaM)-like domain (CaMLD). Some of the human CPVT mutations were reported in this CaMLD. In this study we investigated the molecular mechanism of arrhythmogenesis of CPVT with mutation at CaMLD comparing R2474S and N4103K KI mice.

Methods and Results:
VT and/or Vf were frequently observed after caffeine plus epinephrine infusion in KI mice (R2474S: 100%, N4103K: 43%), but not in WT mice. CaM binding affinity to RyR2 was assessed by incorporation of exogenous CaM labeled with HiLyte Fluor® in isolated saponin-permeabilized cardiomyocytes. The CaM binding affinity was decreased in both R2474S-KI (Kd: 400 nM) and N4103K-KI cells (Kd: 165 nM) compared with WT cells (Kd: 90 nM) in the presence of cAMP. Addition of 1 μM dantrolene (DAN), the zipper of N-terminal and central domain of RyR2, increased the affinity of CaM to RyR2 in R2474S-KI cells, but did not increase that in N4103K-KI cells. Frequency of the Ca
2+
sparks (SpF) was measured in isolated saponin-permeabilized cardiomyocytes. SpF was much higher in KI cells than in WT cells (R2474S-KI: 17.2±6.7, N4103K-KI: 21.5±6.3, WT: 10.6±4.1). Addition of 1 μM DAN to R2474S-KI cells significantly decreases SpF (10.4±5.5), however, DAN did not decrease SpF in N4103K-KI (21.8±6.9). Spontaneous Ca
2+
transient (SCaT) was measured during sequential pacing from 1 to 5 Hz in isolated intact cardiomyocytes. The SCaT was rarely observed in WT cells even with 10 nM isoproterenol, whereas that was observed in 37 % of R2474S-KI and in 33 % of N4103K-KI cells. Addition of DAN to KI cells, decrease frequency of SCaT in R2474S-KI (13 %), however, did not decrease in N4103-KI cells (30 %).

Conclusions:
In CPVT with central domain mutation, domain zipper is effective to inhibit arrhythmias. In CaMLD mutation, structural abnormality might be in the downstream of the N-terminal and central domain switch, so that the DAN is not effective. CaMLD might be a novel therapeutic target of lethal arrhythmias.
Abstract 13840: Stress Myocardial Perfusion Imaging Compared to Coronary Computed Tomography in Patients With Suspected Coronary Artery Disease: an International Randomized Controlled Trial
Authors: Karthikeyan Ganesan , Salobir Barbara G , Jug Borut , Alexanderson Erick , Devasenapathy Niveditha , Vitola Joao , Kraft Otakar , Ozkan Elgin , Paez Diana , Kashyap Ravi
Published: April 2024

Introduction:
Functional imaging by stress myocardial perfusion imaging (MPI) and anatomical imaging by coronary computed tomographic angiography (CTA) are interchangeably used in the initial evaluation of patients with suspected coronary artery disease (CAD). Patients undergoing stress MPI as the initial study may require downstream testing less often when compared to those undergoing CTA.

Methods:
In this international, multicenter, open-label, randomized controlled trial, mildly symptomatic patients who had an intermediate likelihood of having CAD, and asymptomatic patients who were at intermediate risk of cardiac events, were randomized to undergo either initial stress MPI or coronary CTA. Randomization was stratified by site and symptom status. The primary outcome was downstream noninvasive or invasive testing at 6 months. The primary analysis was by intention-to-treat, after adjustment for site, symptom status and physician preference for MPI or CTA. The planned sample size was 500. Because of slow recruitment, the study was stopped at the end of 3 years, without knowledge of outcome data. (NCT01368770)

Results:
Between June 2011 and 2014, we recruited 303 patients (151 MPI and 152 CTA) from 6 centres in 6 countries. Average patient age was 59 years, 28% were diabetic, 80% had chest pain as the presenting symptom, and over 95% underwent the allocated study procedures. The initial test was abnormal in 29% (41/143) of patients in the MPI arm and in 56% (79/141) of the CTA arm.Fewer patients undergoing initial stress MPI had the primary outcome (adjusted OR 0.53, 95% CI 0.29 - 0.94, p=0.03). There were no important differences in the average cost per patient, or the median effective radiation dose between the strategies at 12 months. (Table)

Conclusions:
In the management of patients with intermediate likelihood of CAD, a strategy of initial stress MPI is substantially less likely to require further downstream testing than initial coronary CTA.
Abstract 13842: Fat Free Mass Index is an Important Predictor for Future Cardiac Events in Patients After Cardiac Surgery
Authors: Kinoshita Daisuke , Watanabe Tetsu , Sugai Takayuki , Toshima Taku , Takahashi Tetsuya , Yokoyama Miyuki , Narumi Taro , Shishido Tetsuro , Kubota Isao
Published: April 2024

Introduction:
Sarcopenia is defined as skeletal muscle loss and dysfunction in aging and chronic disease, and associated with increased occurrence of complication after cardiac surgery. Fat-free mass index (FFMI) is used for the clinical diagnosis of sarcopenia. We previously reported sarcopenia evaluated by FFMI were associated with an unfavorable prognosis in patients with chronic heart failure (CHF). However, the impact of sarcopenia on long term prognosis after cardiac surgery remains to be determined

Method and Resultss:
We included 135 patients who underwent cardiac surgery including coronary artery bypass graft and valve replacement in our hospital between 2007 and 2009. We calculated fat free mass (FFM) by using following formula before cardiac surgery: FFM=7.38+0.02908хurinary creatinine (mg/day), and FFM was normalized by square of their height in meter (FFMI). Primary endpoint was major adverse cardiac events (MACE). Secondary endpoint was extended hospital length of stay. There were 3 perioperative deaths and 34 MACEs during the follow-up periods (median 3.8 years). Patients with MACE had significantly lower FFMI than those who without (12.7 vs 14.7 kg/m
2
, p<0.01). Logistic analysis showed that FFMI was independently associated with extended length of hospital stay [Odds ratio: 0.82, 95% confidence interval (CI) 0.65-0.98, p<0.05]. Multivariate Cox proportional hazard analysis revealed FFMI was independently associated with poor outcomes after adjustment of confounding factors (Hazard ratio: 0.86, 95% CI 0.75-0.98, p<0.05). Kaplan-Meier analysis showed that a higher cardiac event rate was observed in patients with low FFMI compared with those who with high FFMI.

Conclusions:
Decreased FFMI was associated with poor outcomes after cardiac surgery.
Abstract 13855: Electrophysiological Substrate and Risk of Mortality in Incident Hemodialysis Patients: Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) Study
Authors: Tereshchenko Larisa G , Oehler Andrew , Meoni Lucy , Ghafoori Elyar , Kim Esther , Rami Tejal , Maly Maggie , Kabir Muammar , Hawkins Lauren , Lima Joao , Jaar Bernard , Sozio Stephen , Estrella Michelle , Parekh Rulan
Published: April 2024

Introduction:
Mortality in end-stage renal disease (ESRD) patients on dialysis is high; sudden cardiac death is the leading cause.

Hypothesis:
Left ventricular hypertrophy (LVH), late potentials on signal averaged ECG (SAECG) and wide spatial QRS-T angle are independently associated with mortality in incident hemodialysis patients.

Methods:
SAECGs were recorded at baseline (within 3-6 months of start of dialysis) in 360 participants [mean age 57.2±13.4 y; 59% male; 73% black; mean left ventricular (LV) ejection fraction (EF) 65.5±12.1%] from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease study, a prospective cohort of incident hemodialysis participants. Spatial mean QRS-T angle was measured on an averaged beat. ECG-LVH was defined as sex-adjusted Cornell product >2440 mm*ms. Echo-LVH was defined as LV mass index >131 g/m2 (M); >113 g/m2 (F). Late potentials were detected on SAECG. All-cause mortality is the primary outcome.

Results:
During 2.4±1.3 years of follow-up, 75 patients died. Cumulative unadjusted mortality was higher in participants with QRS-T angle ≥ 75° (Figure). In Cox regression analyses, stratified by presence of bundle branch block, QRS-T angle ≥ 75° was associated with a greater than two-fold increase in risk for mortality after adjustment for age, sex, race, and BMI [HR 2.62(1.53-4.48); P<0.001]. The association remained significant after the addition to the model: 1) diabetes and prevalent cardiovascular disease [2.47(1.44-4.23); P=0.001], 2) LVEF, QRS duration, and LVH [2.64(1.53-4.55); P<0.0001], and 3) averaged 90-day serum albumin and creatinine [HR 2.29(1.28-4.10); P=0.005]. Abnormal SAECG, ECG-LVH and Echo-LVH were not associated with mortality.

Conclusions:
Spatial QRS-T angle, but not late potentials on SAECG or LVH, is independently associated with mortality after adjustment for both traditional and dialysis-related cardiovascular risk factors in incident hemodialysis.