bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9612: The Left Atrial Emptying Velocity is Significantly Reduced in Patients With Persistent Atrial Fibrillation and A CHADS-Score ≥ 2 in Comparison o Patients With a CHADS-Score < 2
Authors: Butz Thomas , Deising Jill , van Bracht Marc , Prull Magnus , Plehn Gunnar , Trappe Hans-Joachim
Published: April 2024

Aim:
A high CHADS2- as well as CHA2DS2-Vasc-Score on the one hand, and left atrial emptying velocity < 20 cm/s (LAAEV) on the other hand have been separately proposed for risk assessment in patients (pts) with atrial fibrillation (AF). The aim of this study was the analysis of the relation between the CHADS2- and CHA2DS2-Vasc-Score as well as the left atrial emptying velocity (LAAEV), the severity of blood stasis (spontaneous echo contrast, SEC), and presence of LAA thrombi as assessed by transesophageal echocardiography (TOE) in pts with persistent AF.

Methods:
The clinical risk of thromboembolism was assessed with the CHADS2 and CHA2DS2-Vasc-Score in 150 patients (pts) with persistent AF, who had been headed for TOE-guided electrical cardioversion. LAAEV (averaged over 10 beats), SEC, and LAA thrombi were determined by TOE.

Results:
The 150 pts (age 69±13 years) had a mean LAAEV of 34±19 cm/s, 61 pts had no SEC (41%; SEC I: 37 pts; SEC II: 23 pts; SEC III 22 pts), and 29 LAA-thrombi were detected by TOE (LAAEV 50 cm/s: 25 pts, all without LAA-thrombi). The mean CHADS2-Score was 1.9±1.2 (CHADS2 ≥2: 63 %) and the CHA2DS2-Vasc-Score was 3.2±1.8 (CHADS2-Vasc ≥2: 39/46, 89%). There was a moderate inverse correlation between LAAEV and SEC (r: -0.55, p<0.001), and a weak inverse correlation between LAAEV and the CHADS2- (r: -0.28) as well as CHA2DS2-Vasc-Score (r: -0.28). Moreover, Pts with a CHADS-Score ≥ 2 had a significant reduction of the LAAEV in comparison to pts with a CHADS-Score < 2 (29±16 cm/s vs. 41±20 cm/s; p < 0,001).

Conclusion:
This study demonstrated a significant reduction of the LAAEV in pts with a CHADS-Score ≥ 2, and a moderate inverse correlation between the CHADS2-Score and the LAAEV. Due to the fact that low LAAEV (< 20 cm/s) on the one hand, and high CHADS2- as well as CHA2DS2-Vasc-Score on the other hand are predictive for the thromboembolic risk in AF, it might be a promising approach to combine clinical and echocardiographic risk assessments for individual decision making regarding the optimal therapy and risk stratification.
Abstract 9624: Concomitant Early Repolarization is the Independent Predictor for the Occurrence of Sustained Ventricular Tachyarrhythmias or Sudden Death in the Chronic Phase of Acute Myocardial Infarction
Authors: Naruse Yoshihisa , Tada Hiroshi , Harimura Yoshie , Hayashi Mayu , Sato Akira , Sekiguchi Yukio , Hoshi Tomoya , Aonuma Kazutaka
Published: April 2024

Background:
We recently demonstrated that the presence of early repolarization (ER) increased the risk of ventricular fibrillation (VF) ccurrences in the early phase of acute myocardial infarction (AMI). However, it is unknown whether there is an association between ER and VF occurrences in the chronic phase of AMI.

Methods:
This study included 1001 patients with AMI (67±12 years; 762 male; 239 female) who underwent successful percutaneous coronary intervention. The primary endpoint was occurrence of sustained ventricular tachyarrhythmias (VT/VF) or sudden death more than 14 days after AMI onset. We evaluated the presence of ER from the ECG recorded at pre-discharge. ER was defined as a QTS-ST junction elevation of >0.1mV from baseline in at least 2 leads. We also analyzed the localization (inferior or lateral leads), amplitude, morphology (notching or slurring), and ST segment characteristics (upsloping or horizontal/descending) of ER to evaluate the significance of the ER pattern.

Results:
After a mean follow-up of 27.7±17.3 months, 16 (1.6%) patients had an episode of VT/VF or sudden death. The patients with VT/VF or sudden death had a greater prevalence of a left anterior descending culprit artery (75% vs. 45%; p<0.05) and lower left ventricular ejection fraction (39±11% vs. 54±11%; p<0.001) than those without. Furthermore, with the 12-lead ECG analysis recorded pre-discharge, ER was found in 7 (44%) of the patients with VT/VF or sudden death, which was more prevalent than in those without (11%; p<0.01). A multivariate Cox regression analysis revealed that ER (hazard ratio [HR] 6.14; 95% confidence interval [CI] 2.24-16.83; p<0.001) and a left ventricular ejection fraction lower than 35% (HR 15.77; 95% CI 5.69-43.73; p<0.001) were independent predictors of the occurrence of VT/VF or sudden death. As features of the ER pattern, a J-point elevation in the inferior leads, notched morphology of the ER, and ER with a horizontal/descending ST-segment, all were significantly associated with VT/VF or sudden death occurrences.

Conclusions:
The presence of ER increases the risk for VT/VF or sudden death occurrences in the chronic phase of AMI, and may become a useful tool for deciding an indication for an implantable cardioverter defibrillator.
Abstract 9649: Impaired Pulmonary Angiogenesis in Idiopathic Pulmonary Arterial Hypertension is Linked to Abnormal Pericyte Function and Reduced Endothelial-pericyte Interactions
Authors: Yuan Ke , Orcholski Mark , Vladar Eszter C , Axelrod Jeff , Rabinovitch Marlene , de jesus Perez Vinicio
Published: April 2024

Idiopathic pulmonary arterial hypertension (IPAH) is associated with progressive small vessel loss and impaired vascular regeneration. Pericytes are highly specialized vascular cells that directly interact with endothelial cells to provide mural support and promote small vessel maturation and survival. While it is possible that abnormalities in the initiation and maintenance of endothelial-pericyte interactions could contribute to small vessel loss in IPAH, little is known about the role of pericytes in the pulmonary. To circumvent this limitation, we have developed a novel method to purify pericytes from the lungs of failed donors and IPAH patients obtained through the Pulmonary Hypertension Breakthrough Initiative (PHBI). Healthy pulmonary artery endothelial cells (PAECs) on matrigel demonstrated reduced vascular tube formation in the presence of IPAH pericytes compared to control (P<0.0001). The vast majority of IPAH pericytes not only failed to reach and attach themselves to endothelial tubes but also had abnormalities in adhesion, motility and cell polarity. Disruption of Wnt/planar cell polarity (PCP) can contribute to both PAEC loss and impaired tube formation in pulmonary angiogenesis. Given the discrete adhesion, motility and polarity defects of IPAH pericytes, disruption in Wnt/PCP pathway could also contribute to the phenotypic differences observed between healthy and IPAH pericytes. To begin exploring this possibility, gene expression pattern of Wnt ligands and receptors in healthy pericytes and PAECs alone and after co-culture were characterized by qRT-PCR. Compared to single cultures, Wnt5a gene expression was increased in PAECs while an increase in both Vangl1 and ROR2 were seen in pericytes. PAECs with Wnt5a-knockout cannot recruit healthy pericytes in would healing assay as well as in 3D collagen gels. Given that Wnt5a is a known ligand of Wnt/PCP that triggers intracellular signaling through the surface receptors Vangl1 and ROR2 receptors, these preliminary studies strongly suggest that impaired pericyte recruitment to pulmonary vessels resulting from disruption of Wnt/PCP signaling may result in progressive vessel loss and impaired regeneration in IPAH.
Abstract 9664: Utilization Patterns of Anticoagulants in Non-Valvular Atrial Fibrillation after the entry of Novel Oral Anticoagulants in the United States
Authors: Hamilton Melissa , Kawabata Hugh , Liu Xianchen , Brixner Diana , Biskupiak Joseph
Published: April 2024

Introduction:
Anticoagulants including warfarin and novel oral anticoagulants (NOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. Limited data are available on real-world use of warfarin and NOACs in these patients since the entry of NOACs into the US market in October, 2010.

Hypothesis:
Warfarin and NOACs are prescribed for stroke prevention differentially based on patient characteristics.

Methods:
Incident cases of NVAF were identified from GE electronic medical records database between 11/2010 and 08/2011 based on ICD-9 codes 427.31 and 427.32. Baseline characteristics were obtained from medical record history prior to diagnosis. Patients were assessed over 6 months for initiation of warfarin or NOAC (dabigatran or rivaroxaban). Factors associated with anticoagulant initiation and NOAC initiation were examined using multivariate logistic regression analyses.

Results:
Among 19,730 NVAF patients, mean age was 70.8 years, 45.5% were female, and 36.5% initiated an anticoagulant (31.0% warfarin and 5.5% NOAC). CHADS2 score differed across treatment groups with CHADS2 ≥2 found in 47.9%, 45.6% and 36.3% of patients receiving warfarin, NOACs, and no anticoagulants, respectively (p < 0.001). Age, prescriber type, hypertension, diabetes, CHF, prior stroke/TIA, prior MI, and history of GI or other bleeding were significantly associated with the use of anticoagulants. NOAC use was more likely than warfarin in patients with hypertension (OR=1.19), history of GI bleeding (OR=1.40) and prior aspirin use (OR=1.81) but less likely in those with history of CHF (OR=0.70).

Conclusions:
Since the entry of NOACs, over 60% of newly diagnosed NVAF patients did not receive anticoagulants despite 36% of those patients having CHADS2 score ≥2. GI bleeding history, CHF, and prior aspirin use were major clinical factors associated with NOAC use. Further research is warranted to examine changes in anticoagulant treatment over time.
Abstract 9668: Comprehensive Analysis of Intravascular Ultrasonic and Angiographic Morphology of Culprit Lesions Between ST-Segment Elevation Myocardial Infarction and Non-ST-Segment Elevation Acute Coronary Syndrome
Authors: Takaoka Naoko , Tsujita Kenichi , Kaikita Koichi , Hokimoto Seiji , Mizobe Michio , Nagano Masahide , Nakayama Naoki , Horio Eiji , Sato Koji , Yoshimura Hiromi , Kojima Sunao , Tayama Shinji , Sugiyama Seigo , Nakamura Sunao , Ogawa Hisao
Published: April 2024

Background:
Rupture of vulnerable plaque is a major cause of acute coronary syndrome (ACS), with some clots being partially or totally occlusive. However, it is not clear why some plaque ruptures lead to ST-segment elevation myocardial infarction (STEMI), whereas others cause non-ST-segment elevation ACS (NSTEACS).

Methods:
A consecutive 158 ACS pts whose culprit lesions imaged by preintervention intravascular ultrasound (IVUS) were enrolled (STEMI=81; NSTEACS=77). IVUS and angiographic findings of culprit lesions, and clinical demographics were compared between the groups.

Results:
Pts’ characteristics were identical except lower rate of prior statin use in pts with STEMI (20% vs 44%, p=0.001). Angiographic complex Ambrose lesion and thrombus were more common in STEMI than in NSTEACS (83% vs 62%, p=0.002; 51% vs 5%, p<0.0001, respectively). In contrast, SYNTAX score was lower in STEMI (9±5 vs 12±7, p=0.01). In pts with STEMI, culprit echogenicity on IVUS was more hypoechoic (63% vs 40%, p=0.01), and the incidence of plaque rupture, attenuation and “microcalcification (granular calcification with attenuation)” were higher (53% vs 18%, p<0.0001; 86% vs 68%, p=0.01; 75% vs 61%, p=0.04, respectively). Further, the max area of ruptured cavity, echo lucent zone and arc of microcalcification were significantly greater in STEMI compared with NSTEACS (1.8±1.0mm
2
vs 1.1±0.9mm
2
, p=0.006; 1.5±0.7mm
2
vs 1.2±0.8mm
2
, p=0.004; 100±55° vs 77±51°, p=0.01, respectively). On quantitative and color-coded IVUS, vessel and plaque area were significantly larger at min lumen area (MLA) site in STEMI (16.6±5.4mm
2
vs 14.2±5.5mm
2
, p=0.003; 13.9±5.1mm
2
vs 11.6±5.2mm
2
, p=0.003, respectively) and at max vessel area site (20.2±5.4mm
2
vs 18.0±6.4mm
2
, p=0.007; 13.7±4.1mm
2
vs 12.2±5.6mm
2
, p=0.02, respectively), leading to larger necrotic (6.8±3.8mm
2
vs 4.8±3.9mm
2
, p=0.04) and lipidic (1.5±0.6mm
2
vs 1.1±0.6mm
2
, p=0.02) tissue area at MLA site in STEMI as well as fibrotic tissue (7.3±2.5mm
2
vs 5.7±2.2mm
2
, p=0.03).

Conclusion:
Morphological feature (outward vessel remodeling and IVUS vulnerability [e.g. greater ruptured cavity, larger necrotic and lipidic tissue, and microcalcification]) of culprit lesions might relate to clinical presentation of pts with ACS.
Abstract 9701: A Novel Adipocytokine Chemerin Stimulates Proliferation and Hypercontractility of Vascular Smooth Muscle: Implication for Pathogenesis of Obesity-related Hypertension
Authors: Yamawaki Hideyuki , Takai Mizuho , Oda Mayuko , Okada Muneyoshi , Hara Yukio
Published: April 2024

Chemerin is a recently identified adipose tissue-derived cytokine (adipocytokine) which plays roles in inflammatory responses of immune cells such as dendritic cells and macrophages as well as differentiation and metabolisms of adipocytes. Chemerin acts as a chemoattractant for the immune cells, while it induces differentiation of adipocytes and glucose tolerance. Blood chemerin level increases in patients with obesity, and correlates positively with several key factors of metabolic syndrome such as body mass index and triglyceride level. Since blood chemerin level also correlates positively with systolic blood pressure in the obese subjects, we hypothesized that chemerin might relate to pathogenesis of obesity-related hypertension. To test the hypothesis, we examined the effects of chemerin on proliferation and contractility of vascular smooth muscle which play key roles in the development of hypertension. In cultured rat mesenteric arterial smooth muscle cells (SMCs), chemerin (1-100 ng/ml, 24h) stimulated proliferation in a concentration-dependent manner (n=8, P<0.01). Chemerin (100 ng/ml, 20 min) stimulated phosphorylation of Akt (n=8, P<0.05), and an Akt inhibitor prevented the chemerin-induced SMCs proliferation (n=4). Chemerin produced oxidant radicals in SMCs, and an anti-oxidant drug, N-acetyl-L-cysteine inhibited SMCs proliferation (n=6) and Akt phosphorylation (n=4, P<0.05). In rat isolated mesenteric artery, chemerin (100 ng/ml, 30 min) augmented noradenaline (1 nM-1 μM)-induced concentration-dependent contraction (n=6, P<0.05). The effect was higher in endothelium-intact artery than endothelium-denuded artery (n=7), and was normalized by an endothelin type A receptor blocker, BQ123 (n=13). Chemerin had no influence on noradrenaline-stimulated endothelial nitric oxide production (n=10). The present results for the first time demonstrated that chemerin stimulates proliferation of vascular SMCs via oxidative-stress-dependent Akt activation. It is also demonstrated that chemerin mediates hypercontractility of isolated mesenteric artery likely via endothelial-derived endothelin-1. The results may represent chemerin as a new adipocytokine to understand the link between obesity and hypertension.
Abstract 9710: Contractile Reserve Assessed by Three-Dimensional Global Circumferential Strain as a Predictor of Cardiovascular Events in Patients with Idiopathic Dilated Cardiomyopathy
Authors: Matsumoto Kensuke , Tanaka Hidekazu , Tatsumi Kazuhiro , Sawa Takuma , Mochizuki Yasuhide , Motoji Yoshiki , Imanishi Junichi , Miyoshi Tatsuya , Hiraishi Mana , Kaneko Akihiro , Tsuji Takayuki , Ryo Keiko , Fukuda Yuko , Kawai Hiroya , Hirata Ken-ichi
Published: April 2024

Background:
Two-dimensional global circumferential strain (GCS) from mid-left ventricular (LV) short-axis view has been reported as a powerful predictor of cardiac events and appeared to be a better parameter than ejection fraction in heart failure (HF) patients. However, this technique is limited to two-dimensional tomographic imaging planes, which may oversimplify the complexities of left ventricular function. On the other hand, novel three-dimensional (3-D) speckle-tracking system can quantify 3 different strains simultaneously from all 16 LV segments. Accordingly, our objective was to investigate the ability of GCS with dobutamine stress using 3-D speckle-tracking to predict cardiac events in HF patients with idiopathic dilated cardiomyopathy (DCM).

Methods:
We prospectively recruited 54 consecutive DCM patients with ejection fraction of 34±8%. We measured GCS, global radial, and longitudinal strains using 3-D speckle-tracking echocardiography at baseline and during dobutamine infusion (20µg/kg/min). Event-free survival was pre-specified as primary end points of death from worsening HF, hospitalization for deteriorating HF, and was tracked over 12.3 months.

Results:
The primary endpoint occurred in 7 (17%) of patients. Of individual measures, the increase in 3-D GCS with dobutamine stress (ΔGCS) ≤2.71% was the best predictor of cardiac events with sensitivity of 90%, specificity of 81%, and the area under the curve of 0.927 (p<0.001). In multivariate Cox proportional hazard model, ΔGCS was the strongest predictor of cardiac events (hazard ratio: 0.375, 95% confidential interval: 0.202-0.695, p=0.002). Furthermore, patients with ΔGCS>2.71% had a significantly better prognosis than those with ΔGCS≤2.71% (Log rank p<0.001).

Conclusion:
3-D GCS with dobutamine stress would have potential to predict cardiac events in HF patients with DCM. These observations may have clinical implications for management of such patients.
Abstract 9719: Overexpressed Phoshodiesterase 3A1 Protects the Heart against Angiotensin II-induced Cardiac Injury via Regulating Interaction between β-adrenergic and Angiotensin II Signaling Pathways
Authors: Oikawa Masayoshi , Iwaya Shoji , Yan Chen , Takeishi Yasuchika
Published: April 2024

BACKGROUND: Angiotensin II (AngII) has critical roles in progression of cardiac hypertrophy and fibrosis, leading to subsequent heart failure. Accumulating evidence suggests that there are direct interactions between β-adrenergic and AngII signaling pathways, and β-blocker treatment protects hearts against AngII-induced cardiac injury. Phosphodiesterase 3A (PDE3A) inhibits β-adrenergic receptor (βAR)/protein kinase A (PKA) axis by metabolizing cAMP. Therefore, we hypothesized that overexpressed PDE3A has cardioprotective effects against AngII-induced cardiac injury by regulating AngII signaling.

METHODS AND RESULTS: To induce cardiac injury, AngII (800 ng/kg/min) was continuously infused using osmotic mini-pump for 10 days in wild-type (WT) mice and transgenic (TG) mice with cardiac-specific expression of exogenous PDE3A1. AngII stimulation increased heart weight/body weight ratio by 32% in WT hearts compared with vehicle hearts (5.6±0.5 mg/g vs. 4.3±0.1 mg/g, P<0.05), whereas by 5% in TG hearts (5.8±0.6 mg/g vs. 5.5±0.8 mg/g, ns). Echocardiography revealed that AngII lead to cardiac hypertrophy in WT hearts compared to vehicle hearts (wall thickness, 12.4±1.5 mm vs. 8.2±0.7 mm, P<0.05), but not in TG hearts (10.4±1.5 mm vs. 9.3±0.3 mm, ns). Moreover, AngII-induced cardiac fibrosis was also inhibited in TG hearts compared to WT hearts (4.2±1.1% vs. 6.9±2.6%, P<0.05). Interestingly, basal expression levels of transforming growth factor-β (TGFβ) as well as phosphorylated-phospholamban were inhibited in TG hearts compared to WT hearts, suggesting that overexpressed PDE3A regulated AngII/TGFβ and βAR/PKA axis.

CONCLUSIONS: We thus conclude that PDE3A inhibits AngII-induced cardiac hypertrophy and fibrosis via regulating the interaction between β-AR/PKA and AngII/TGFβ axis.
Abstract 9748:
In Vivo
Cardiac Cellular Reprogramming Efficacy is Enhanced by Angiogenic Preconditioning of the Infarcted Myocardium
Authors: Mathison Megumi , Gersch Robert , Nasser Ahmed , Korman Mallory , Fourman Mitchell , Hackett Neil , Qian Li , Srivastava Deepak , Shroyer Kenneth , Ma Yupo , Crystal Ron , Rosengart Todd
Published: April 2024

A new
in situ
cellular reprogramming strategy demonstrated to convert fibroblasts into cardiomyocytes may represent an ideal cardiac regenerative therapy, obviating challenges inherent in stem cell implantation. We hypothesized that this strategy would be enhanced by angiogenic pretreatment of myocardial scar targeted by this treatment.

Methods:
The efficacy of lentivirus-mediated delivery of Gata4, Mef 2c and Tbx5 to transdifferentiate rat fibroblasts into induced cardiomyocytes (iCMs; Ieda
et. al
.,
Cell
. 2010; 142: 375-386) was validated by i
n vitro
FACS and immunofluorescence studies. Adult male Fischer 344 rats (n=12/group) then underwent coronary ligation and intramyocardial administration of AdVEGF-All6A+, an adenovirus encoding all three major isoforms of VEGF, or AdNull, an empty expression cassette vector. Three wks later, 6 animals/group received lentiviruses each encoding Gata4, Mef 2c or Tbx5 (GMT), or encoding only GFP. Echocardiograms were performed prior to and 3d after coronary ligation, at the time of GMT or GFP administration (baseline), and 2 and 4 wks later.

Results:
In vitro
studies demonstrated rat fibroblast conversion into iCMs based on cellular morphology and expression of markers including cardiac troponin T. Echo analyses in the myocardial infarction model above demonstrated significant improvement from baseline for cardiac ejection fraction (EF) 2 and 4 wks after GMT
vs
GFP administration (EF% change 4 wks after treatment: 12% ± 9%
vs
-7% ± 10%, p<0.01). Eight GFP-treated but no GMT animals demonstrated decreased EF during this interval (p<0.01). Moreover, improvement in EF was 4 times greater in GMT/VEGF
vs
GMT/AdNull animals (17% ± 7 %
vs
4% ± 3%, p<0.01). No significant change in EF was detected in animals treated with AdVEGF-All6A+ without GMT.

Conclusion:
Angiogenic pretreatment of myocardial scar significantly enhances the efficacy of cellular reprogramming after myocardial infarction.
Abstract 9763: Brain-targeted Intranasal Administration of Viral Inhibition Peptide of Toll-like Receptor 4 Improves Survival and Prevents Left Ventricular Remodeling Via Sympathoinhibition in Ischemia-induced Heart Failure
Authors: Kishi Takuya , Hirooka Yoshitaka , Sunagawa Kenji
Published: April 2024

[Backgrounds] Abnormal sympathoexcitation causes left ventricular (LV) remodeling and worsen the prognosis of ischemia-induced heart failure (HF). Recent studies have suggested that inflammation in the brain induces sympathoexcitation in HF. We previously demonstrated that brain inflammatory cascade mediated by Toll-like receptor 4 (TLR4) is activated in HF associated with sympathoexcitation. However, brain-specific inhibitory agent of TLR4 has not been available. The aim of the present study was to investigate whether intranasal administration of viral inhibition peptide of TLR4 (VIPER) could inhibit brain-specific TLR4 or not, and whether the brain-targeted inhibition of TLR4 could improve survival rate and prevent LV remodeling via sympathoinhibition in ischemia-induced HF or not. [Methods and Results] Sprague-Dawley rats with HF by coronary artery ligation were initiated the treatment with a dairy intranasal administration of VIPER (VIP), dairy intraperitoneal administration of VIPER (IP) or vehicle (Veh) just after the operation. At day 1, the expressions of TLR4, MyD88 (second messenger of TLR4), and nuclear factor κB (NFκB) in the brain were already significantly lower in VIP than in IP and Veh. These effects in VIP group were confirmed continuously in terms of the treatments. At day 7, urinary norepinephrine excretion (UNE; parameter of sympathoexcitation) was significantly lower and LV end-systolic dimension (LVESD) were significantly smaller in VIP than in Veh (uNE; 1.6±0.2 μg/day vs. 2.5±0.2 μg/day, LVESD; 2.9±0.3 mm vs. 4.8±0.2 mm, n=15 for each, p<0.05 for each). At day 30, the survival rate was significantly higher in VIP than in Veh (84 % vs 61 %, P<0.05). All of these beneficial results in VIP group were not obtained in IP group. [Conclusion] Intranasal administration of viral inhibition peptide of TLR4 is able to inhibit brain-specific TLR4, and improves survival rate and prevents LV remodeling via sympathoinhibition in ischemia-induced HF. This method has a potential to be a novel treatment for ischemia-induced HF with sympathoinhibition.
Abstract 9794: Load Dependency of Right Ventricular Performance is a Major Factor to be Considered in Decision Making Prior to Ventricular Assist Device Implantation
Authors: Dandel Michael , Potapov Evgenij , Krabatsch Thomas , Stepanenko Alexander , Löw Alexandra , Vierecke Juliane , Knosalla Christoph , Hetzer Roland
Published: April 2024

Background
Left ventricular assist devices (LVADs) provide better quality of life than biventricular devices (BVADs), but it is a challenge to evaluate right ventricular (RV) function and to predict its time-course after LV support. Severe RV failure after LVAD implantation appeared related to pre-operative RV geometry and tricuspid regurgitation (TR) which are highly load sensitive parameters. We assessed the impact of load dependency on RV performance before and after LVAD implantation aiming to improve pre-operative decision making.

Methods
We evaluated our patients who received a LVAD after 1/2006. RV anatomic and functional parameters collected prospectively before LVAD implantation and invasively collected data on pulmonary hemodynamics were tested for relationship with post-implant RV function and patient outcome. Echocardiography including tissue Doppler and 2D strain imaging was used to evaluate RV size, geometry and function.

Results
After LVAD implantation 45 (9.5%) of 475 evaluated patients showed worsening of RV function which necessitated a mechanical support also for the RV. Whereas RVEF was similar in patients with and without stable post-operative RV function there were significant differences in pre-operative long/short axis (L/S) ratio, tricuspid annulus peak systolic velocity (TAPSm) peak global strain rate (RVSSr),RV/right atrial pressure gradient (ΔP-RV/RA) and pulmonary arterial pressure (PAP) between the two patient groups (p < 0.05). The highest predictive values (up to 93.5%) for RV failure after LVAD insertion were found for pre-operative L/S ≥ 0.6, TAPSm < 8cm/s, and peak RVSSr < 0.7/s in patients with maximum ΔP-RV/RA < 35mmHg. L/S, TAPSm and RVSSr also showed high predictive values for RV failure in patients with preoperative TR > grade II and PAP < 50mmHg. L/S < 0.6, TAPSm ≥ 8cm/s, and peak RVSSr ≥ 0.7/s in patients with maximum ΔP-RV/RA ≥ 35mmHg showed high predictive values (≥ 92%) for postoperative freedom from RV failure.

Conclusion
RV geometry and velocity of contraction before LVAD implantation are highly predictive for postoperative RV function if preoperative PAP and TR are also considered. RV L/S ratio, TAPSm and RVSSr, in connection with maximum ΔP-RV/RA, can improve decision making before VAD implantation.
Abstract 9871: Enhanced Active Metabolite Generation and Platelet Inhibition With Prasugrel Compared to Clopidogrel Regardless of Genotype in Thienopyridine Metabolic Pathways
Authors: Braun Oscar Ö , Angiolillo Dominick J , Ferreiro José L , Jakubowski Joseph A , Winters Kenneth J , Effron Mark B , Duvvuru Suman , Costigan Timothy M , Sundseth Scott S , Walker Joseph R , Saucedo Jorge F , Kleiman Neal S , Erlinge David , Varenhorst Christoph
Published: April 2024

Background:
Clopidogrel (Clop) response is modulated by genetic polymorphisms. In particular, the
CYP2C19*2
allele has been associated with impaired response, while conflicting results have been reported for
CYP2C19*17, ABCB1
and
PON1
genotypes. We assessed the impact of
CYP2C19, PON1
and
ABCB1
polymorphisms on Clop and prasugrel (Pras) pharmacodynamic (PD) response and pharmacokinetic (PK) profile.

Methods:
Aspirin-treated patients (n=194) with coronary artery disease enrolled in two independent, prospective, randomized, multicenter studies comparing Clop (75 mg) and Pras (10 mg) were genotyped and classified according to standard definitions of predicted
CYP2C19
metabolizer phenotype (ultra metabolizers (UM) = *17 carriers; reduced metabolizers (RM) = *2 carriers). PD assessments were made using LTA, VerifyNow P2Y12 and VASP-PRI (platelet reactivity index) after 14 days of maintenance dosing. PK parameters of active metabolite (AM) exposure of both Clop and Pras were calculated in a cohort of 98 patients.

Results:
For Clop, genetic variants in
CYP2C19
, but not
ABCB1
or
PON1
, affected the PK and PD. For Pras, none of the measured genetic variants affected PK or PD. Compared with Clop, platelet inhibition with Pras was greater even in
CYP2C19
UM phenotype (figure). Pras generated more AM and achieved greater platelet inhibition than Clop irrespective of
CYP2C19, ABCB1
and
PON1
polymorphisms.

Conclusion:
Pras generated higher levels of AM and achieved greater platelet inhibition than Clop in all
CYP2C19
genotypes. Neither
ABCB1
nor
PON1
genetic variation affected Pras or Clop PD or PK response.
Abstract 9934: Biventricular Assist Device May be Superior to Left Ventricular Assist Device for Crash and Burn Patients
Authors: Moriguchi Jamie , Kansara Pranav , Kransdorf Evan , Kittleson Michelle , Patel Jignesh , Runyan Carmelita , Olay Charito , Jocson Rhodora , Czer Lawrence , Esmailian Fardad , Kobashigawa Jon
Published: April 2024

Purpose:
Over 15,000 left ventricular assist devices (LVADs; HeartMate I and II) have been implanted world-wide as bridge to transplant or destination in the last decade and appears to be the device of choice. However, the 1 year survival and success to transplant rates are not uniform across the INTERMACS profile spectrum. Current 6 month survival for INTERMACS profile 1 patients undergoing VAD support as bridge to transplant is 60%. We reviewed our more recent experience with both biventricular assist device (BiVAD) and LVAD support to compare the effectiveness and success rates for these two bridging modalities in this critically-ill cohort of patients.

Methods:
Between Jan 2007 and Mar 2012, we reviewed 56 INTERMACS profile 1 patients. 32 patients who appeared to have adequate right ventricular function received the LVAD (20 HeartMate I and 12 HeartMate II) alone while the remaining 24 patients were supported with a pneumatic BiVAD. Successful bridge to transplant, recovery and ongoing support at 6 months were analyzed among these groups.

Results:
21/24 BiVAD patients vs 11/32 LVAD pts (88% vs 34%, p<0.001) were successfully transplanted or explanted due to recovery of cardiac function. Of the LVAD patients, 7/20 HeartMate II patients vs 4/12 HeartMate I patients (35% vs 33%, p=0.93) were successfully transplanted or explanted due to recovery of cardiac function. Multivariate analysis suggested that inotropic support more than 14 days post VAD implantation in LVAD patients was associated with increased mortality. 2/3 BiVAD deaths and 13/21 LVAD deaths were due to progressive shock, hemorrhage or right ventricular failure. 1-year survival post transplant was 18/20 (90%) in the BiVAD group and 11/11 (100%) in the LVAD group.

Conclusions:
In critically-ill INTERMACS profile 1 transplant candidates, BiVAD support may result in improved outcomes compared to LVAD and could be the device of choice. In these LVAD patients, perceived adequate right ventricular function may be misleading as these are very ill INTERMACS profile 1 patients where subsequent progressive shock, hemorrhage and right ventricular failure are major causes of death.
Abstract 9951: Cardiac GRK2 Inhibition via ARKct Augments 2-adrenergic Receptor-dependent Contractility and Survival Post-Myocardial Infarction
Authors: Lymperopoulos Anastasios , Rengo Giuseppe , Gao Erhe , Bathgate Ashley , Koch Walter J
Published: April 2024

Rationale:
β
1
and

β
2
-adrenergic receptors (βARs) play distinct roles in the heart, e.g. β
1
AR is pro-contractile and pro-apoptotic but β
2
AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade in vivo might enhance the pro-contractile and anti-apoptotic signaling of the cardiac β
2
AR.

Objective:
We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β
2
AR signaling post-myocardial infarction (MI).

Methods and Results:
We crossed β
1
AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a peptide inhibitor of GRK2, and studied the offspring under normal conditions and post-MI. βARKct expression in vivo leads to significantly enhanced β
2
AR-dependent cardiac function, in part via reduction of phosphodiesterase (PDE)4D recruitment to the receptor (ejection fraction in sham-operated, healthy mice: 70+1.1% in βARKct/B1KO`s vs. 59+1.77% in B1KO`s, p<0.05, n=7, and in 4-week post-MI mice: 41.3+3% in βARKct/B1KO`s vs. 25+1.2% in B1KO`s, p<0.05, n=7). In addition, βARKct/B1KO`s have decreased heart dilatation and infarct size, and increased survival at 4 weeks post-MI compared to control B1KO mice. These phenotypic effects are secondary to decreased apoptosis (mediated by Bcl-2 elevation) and increased wound healing-associated inflammation (mediated by NF-κB activation) in βARKct/B1KO hearts very early (at 24 hrs) post-MI vs. B1KO controls.

Conclusions:
GRK2 inhibition via βARKct markedly augments cardiac β
2
AR beneficial (pro-contractile and anti-apoptotic) signaling post-MI, and thus might be useful for β
2
AR agonist drug therapy in heart failure, e.g. in post-MI patients awaiting cardiac transplantation.
Abstract 9962: Carotid Intima-Media Thickness and Carotid Distensibility are Associated with Incident Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Chen Lin Y , Lopez Faye L , Huxley Rachel R , Agarwal Sunil K , Pan Wei , Folsom Aaron R , Alonso Alvaro
Published: April 2024

Background
Increased carotid intima-media thickness (cIMT) and decreased carotid distensibility are associated with an increased risk of myocardial infarction and stroke. It is unclear whether these carotid indices are associated with atrial fibrillation (AF) incidence. In the ARIC cohort, we assessed whether carotid indices are associated with an increased risk of AF and improve risk prediction of AF.

Methods
We included 10,077 (mean age, 56.8 ± 5.7 yrs; 56% female; 24% black) subjects who were followed from 1990-92 through 2009. cIMT, arterial diameter change (ADC), Peterson’s elastic modulus (Ep), Young’s elastic modulus (YEM), and β index were measured using carotid ultrasound in 1990-92. Incident AF cases were identified from ECGs at study exams and hospitalization discharge codes. We used multivariable Cox proportional hazards models to assess association between carotid indices and AF. Using the CHARGE AF score as the benchmark, we determined improvement in model discrimination by estimating the C statistic and calculating the net reclassification improvement (NRI) and integrated discrimination improvement (IDI).

Results
During follow-up (median 17.8 yrs), there were 1,028 incident AF cases. Greater levels of cIMT, Ep, and β index were significantly associated with an increased risk of AF (Table 1). The addition of cIMT and cIMT + plaque improved model discrimination marginally: C statistic (95% CI) improved from 0.795 (0.760-0.830) to 0.796 (0.761-0.831) and 0.797 (0.762-0.832), respectively. Although NRI was not statistically significant, IDI was significant for cIMT (P=0.02) and cIMT + plaque (P=0.005). Ep and β index did not improve model discrimination.

Conclusions
Increased cIMT and decreased carotid distensibility are associated with an increased risk of AF and modestly improve risk prediction of AF. This finding reinforces an emerging viewpoint on AF pathogenesis: AF is not purely an electrical disease, but is also a ‘vascular’ disease.
Abstract 9977: Prognostic Value of Coronary Artery Calcium and Epicardial Adipose Tissue Assessed by Noncontract Computed Tomography
Authors: Kunita Eiji , Yamamoto Hideya , Ustunomiya Hiroto , Oka Toshiharu , Urabe Yoji , Kitagawa Toshiro , Tsushima Hiroshi , Yamazato Ryo , Tomohiro Yasuyuki , Kihara Yasuki
Published: April 2024

Background:
Coronary artery calcium (CAC) and epicardial adipose tissue volume (EATV) as assessed by noncontrast computed tomography (NCT) have demonstrated to be associated with adverse cardiac outcomes. However, it is not well known whether the simultaneous evaluation of CAC and EATV has value in prediction of future cardiac events (CEs).

Methods:
We studied 712 patients (65 ± 11 years, 61% men) referred for NCT, and assessed CAC and EATV. CAC score was measured using Agatston method. Patients were initially assigned to two groups: low (<100 ml) or high (≥100 ml) EATV. Patients were followed up as to the occurrence of CEs (cardiac death, myocardial infarction, unstable angina requiring hospitalization, and late coronary revascularization).

Results:
During a 3.8 ± 1.4 years follow-up period, 44 CEs were documented. The prevalence of CAC (93% vs. 62%, p < 0.001) and high EATV (77% vs. 54%, p = 0.002) were significantly higher in patients with CEs than in those without. In Cox regression analysis, CAC (hazard ratio [HR] 5.44, 95% confidence interval [CI] 1.85-23.4, p = 0.001) and high EATV (HR 2.34, 95% CI 1.16-5.14, p = 0.017) were independent predictors of CEs after adjustment of age, gender, and traditional cardiovascular risk factors. Kaplan-Meier event-free survival curves amongst 4 groups divided by absence or presence of CAC and low or high EATV for CEs are shown in Figure. The CE rates were highest in the high EATV group with CAC compared to other groups. Furthermore, when analyzed in groups with CAC, high EATV was associated with CEs even after adjustment of CAC scores (HR 2.25, 95% CI 1.07-5.17, p = 0.031). In contrast, there was no significant difference in adjusted HRs between low and high EATV groups without CAC.

Conclusions:
The high EATV and the presence of CAC were independent predictors of CEs. Notably, the measurement of EATV in patients with CAC was useful to predict CEs in the near to medium term. The simultaneous evaluation of CAC and EATV can improve prediction of future CEs.
Abstract 9992: Urine Proteome Analysis Allows Establishment of Polypeptide Patterns non-Invasively Reflecting Drug-Mediated Regression of Atherosclerosis in ApoE-/--Mice
Authors: Von Zur Muhlen Constantin , Schiffer Eric , Sackmann Christine , Chen YC , Zúrbig Petra , Mischak Harald , Bode Christoph , Peter Karlheinz
Published: April 2024

Background:
Recently, non-invasive urine proteome analysis established a multimarker proteome approach towards non-invasive detection of atherosclerosis in an ApoE-/--mouse model, and relevance of this proteome pattern was also confirmed in human atherosclerosis. Urine was used since it lacks peptidase activity, which is found in blood and could falsify proteome analysis. Additionally, non-invasive monitoring of anti-atherosclerotic therapy with statins is of high clinical interest, and could be an important tool for guiding medical therapy. We therefore aimed to identify urinary polypeptides reflecting statin therapy in the ApoE-/--mouse model.

Methods and Results:
Urine of ApoE-/--mice either on high fat diet (HFD) or chow diet (CD) was collected over 15 weeks; each group was divided into subgroups with or without statin therapy applied by oral gavaging (HFD+S and HFD-S). Capillary electrophoresis mass spectrometry (CE-MS) of urine samples identified 5 polypeptides specifically reflecting statin treatment, resulting in a shift towards a more “healthy” polypeptide pattern until week 12. Sequencing of the discovered polypeptides identified fragments of α1-antitrypsin, EGF, kidney androgen regulated protein (KAP) and napsin. In histology, plaque size was significantly reduced by statin treatment, and presence of marker proteins in atherosclerotic plaques was confirmed by immunohistochemistry. Furthermore, urinary excretion levels of α1-antitrypsin fragments significantly correlated with intraplaque α1-antitrypsin content, mirroring plaque protein expression in the urine proteome.

Conclusions:
Urine proteome analysis allows discovery of novel biomarkers for the non-invasive monitoring of an anti-atherosclerotic therapy with statins in an ApoE-/--mouse model. The established multimarker proteome pattern reflects regression of plaque size in histology, and marker excretion levels also correlate with their expression in immunohistochemistry. This approach allows monitoring of atherosclerosis progression and statin treatment in mice, and thus promises to be an important and clinically relevant tool for monitoring and guiding of established but even more so of novel developments of anti-atherosclerotic drugs.
Abstract 17984: Protective Role of Dicer in Macrophages During Atherogenesis
Authors: Wei Yuanyuan , Heyll Kathrin , Weber Christian , Schober Andreas
Published: April 2024

Atherosclerotic lesion development is characterized by the subendothelial accumulation of lipid-laden macrophages. It is known that microRNAs (miRs) are generated by the RNase Dicer and play important roles in macrophage function by negatively regulating post-transcriptional gene expression. Previously, we found that macrophage-derived miR-342-5p enhances atherosclerosis by fostering inflammatory macrophage activation. However, the impact of Dicer-dependent miR expression in macrophages during atherosclerosis is unclear.

To study the role of Dicer in macrophages in atherosclerosis, we fed Apoe-/- mice with a myeloid cell-specific deletion of Dicer (LysMCre-Dicerflox) and littermate controls (LysMCre-DicerWT) a high cholesterol diet (HCD) for 3 months. Dicer deletion in myeloid cells was confirmed in bone marrow-derived macrophages isolated from LysMCre-Dicerflox mice by real-time PCR. The lipid deposition in the aortas was increased by 50% in LysMCre-Dicerflox (3.3±0.3%) compared to LysMCre-Dicerwt mice (2.1±0.3%) (p = 0.01, n = 13). The differential blood counts and the serum cholesterol and triglyceride levels were not altered between two groups. We found that 79 miRs, including those highly expressed in macrophages (e.g., miR-146a and miR-223), were down-regulated in LysMCre-Dicerflox aortas compared to controls after 3 months of a HCD (p < 0.05, n = 3) using a miR real-time PCR array. In aortas from LysMCre-Dicerflox mice, 471 genes were up-regulated as determined by whole-genome gene expression profiling using Agilent Mouse Microarrays (p < 0.05, n = 3-4). Genes involved in fatty acid and lipid metabolism were enriched among the up-regulated genes as analyzed by GeneGo MetaCore. Up-regulation of Plg, Ptges2, Eci1, Impa2, Acox2, Thrsp, and the lipid droplet-related genes plin-1, -2, -5 and Cidea was confirmed by real-time PCR. Whereas Plg was predicted to be a target of miR-223 by Targetscan, plin-1, -2, and Ptges2 were identified as potential targets of miR-146a using miRanda.

These data indicate a protective role of Dicer during atherogenesis by inhibiting lipid metabolism in lesional macrophages through miRs. Thus, regulation of the lipid metabolism in macrophages might be a critical step in the development of atherosclerosis.
Abstract 17990: Ectopic Fat is Associated With Gender-specific Reductions in Left Ventricular Myocardial Perfusion Index During Dobutamine Stress
Authors: Hall Michael E , Brinkley Tina E , Morgan Timothy , Hamilton Craig A , Jordan Jennifer H , Stacey Richard B , Chugtai Haroon , Soots Sandra , Little William C , Hundley William G
Published: April 2024

Background:
Obesity and visceral adiposity are increasingly recognized risk factors for cardiovascular disease. Visceral fat may reduce myocardial perfusion by impairing endothelial function. Accordingly, we evaluated the association of visceral fat and quantitative myocardial perfusion during peak dose dobutamine stress using MRI.

Methods:
We evaluated MRI myocardial perfusion index (MPI) in 59 individuals at risk for their first episode of symptomatic heart failure with a left ventricular (LV) ejection fraction >45% and no MRI evidence of previous myocardial infarction or inducible ischemia. MPI was calculated after the first pass of gadolinium (by dividing the upslope of the signal intensity over time curve of the mid LV septum by the upslope of the LV cavity blood curve) after dobutamine and atropine were administered to achieve 80% of the maximum predicted heart rate response for age. Pericardial, subcutaneous (SQ), intraabdominal (IA) and retroperitoneal (RP) fat volumes were quantified using validated MRI techniques. All analyses were blinded to participant identifiers. Pearson’s coefficients were determined and a p-value of < 0.05 was considered significant.

Results:
Participants averaged 66 ± 7 years in age; 34% were men, 27% African American, 43% diabetic, and 93% were hypertensive. Overall, pericardial, IA, and RP fat were negatively associated with MPI (Table). No fat depots were associated with reduced MPI in men. However pericardial (r=-0.57, p=0.02), IA (r=-0.34, p=0.04) and SQ fat (r=-0.42, p=0.01) were all negatively associated with MPI in women.

Conclusions:
Higher pericardial, IA and RP fat volumes are associated with reduced LV myocardial perfusion at peak dobutamine stress in women. These findings suggest visceral fat may contribute to abnormal microcirculatory coronary arterial perfusion syndromes, explaining why some women may exhibit more anginal symptoms despite typically lower grade coronary artery stenoses than men.
Abstract 180: Mild Systemic Hypothermia Induced by Preferential Brain Cooling Suppresses Cardiovascular Functions More Significantly Than That Induced by Systemic Cooling in a Rabbit Model
Authors: Guan Jun , Diao Mengyuan , Lin Zhaofen , Zhang Zhe , Xiao Yan
Published: April 2024

Introduction:
The optimal target temperature for preferential brain cooling is unclear.

Hypothesis:
Preferential brain cooling suppresses cardiovascular functions more significantly than systemic cooling with the same core body temperature (Tc) target of therapeutic mild hypothermia (TMH).

Methods:
After anesthesia and instrumentation, five rabbits first received preferential brain cooling by using a semiconductor neck cooling collar starting from 37°C of Tc to the target of 34°C. Then after rewarming to 37°C of Tc by warming blanket, the animals received systemic cooling with the same Tc target by ice pads and fan. Another five rabbits first received systemic cooling, and then received neck cooling with the same procedures. Mean arterial pressure (MAP), heart rate (HR), left ventricular systolic pressure (LVSP), LV dp/dt, LV -dp/dt, respiratory rate (RR), PetCO2, brain temperature (Tb) and Tc were continuously monitored and recorded at 0.2°C interval of Tc during hypothermia in all animals. For monitoring Tb and Tc, thermoprobes were placed into brain parenchyma and rectum respectively. Paired t-test were used to compare measurements at 37°C and 34°C of Tc.

Results:
During systemic cooling, Tb decreased in parallel with Tc. Only HR decreased significantly from 249±13 bpm at 37°C to 216±14 bpm at 34°C, P<0.001. No significant changes were detected in MAP, dp/dt, -dp/dt, LVSP, RR and PetCO2. In contrast, during neck cooling, Tb decreased 3.1±1.2°C more than Tc at 34°C of Tc. At meantime, MAP decreased significantly from 98±8 mmHg at 37°C to 84±7 mmHg at 34°C, P<0.001. HR, dp/dt, LVSP also decreased significantly, all p<0.01. RR, PetCO2 and -dp/dt did not change significantly. Pearson correlation analysis showed MAP was more closely related to Tb than to Tc, the coefficients were 0.539 (P<0.001) and 0.158 (P=0.002) respectively. Multiple linear regression analysis also showed a higher standardized coefficient of Tb than that of Tc for MAP (0.667 vs. -0.224), indicating that Tb has a greater effect on MAP than Tc.

Conclusions:
Preferential brain cooling suppresses cardiovascular functions more significantly than systemic cooling when achieving the same core body temperature target of TMH. Brain temperature has a greater impact on MAP than core body temperature during TMH.