bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9257: The Effect of Massachusetts Health Reform on Racial Disparities in 30-Day Readmissions for Acute Myocardial Infarction
Authors: Lasser Karen E , McCormick Danny , Chu Chieh , D'Amore Meredith , Kressin Nancy , Hanchate Amresh
Published: April 2024

Background:
Following Massachusetts (MA) health reform, the percent of uninsured residents fell from 8.4% to 3.4%, with larger gains among minorities. Prior studies have not examined the effect of this policy change on 30-day readmission rates for myocardial infarction (MI). We hypothesized that racial disparities in such admissions would decline in MA among adults age 18-64 following the reform.

Methods:
Using MA inpatient discharge data from 2004-2009, we compared 30-day readmissions after hospitalization for acute MI among white and black patients, prior to and following reform implementation. We defined the pre-reform period as 2004-2006, and the post-reform period as 2008-2009. We used chi-square tests to compare 30-day readmissions for MI between groups. Controlling for age, gender, and Charlson Comorbidity Score, we used multiple logistic regression to calculate risk-adjusted odds of 30-day readmission. Treating adults > 65 (who are mostly covered by Medicare and thus unaffected by the reform) as the comparison cohort, we used difference-in-difference specification to identify the post-reform change adjusted for secular changes unrelated to reform.

Results:
Pre-reform, black patients age 18-64 had higher readmission rates than white patients (18.1% vs. 11.2%; p=0.001), this difference persisted post-reform (17.0% vs. 10.2%; p <0.001). Among patients age ≥65, in the pre-reform period, black patients also had higher readmission rates than whites (29.2% vs. 23.9%; p=0.02); this also persisted post-reform (27.8% vs. 22.2%; p=0.01). The readmission rate for blacks age18-64 did not change significantly from pre-reform to post-reform (18.1% vs. 17.0%, adjusted OR (AOR), 0.9; 95% CI, 0.6- 1.3); nor did the readmission rate for blacks, age ≥65, change significantly (29.2% vs. 27.8%, AOR, 0.8; 95% CI, 0.6- 1.2). The difference in the change in AOR for blacks pre- and post- reform, age 18-64, and the change in AOR for blacks pre- and post- reform, age > 65 (“difference-in-difference”) was not significant (p=0.6).

Conclusions:
Black patients were more likely than whites to be readmitted after hospitalization for MI, both before and after health reform. MA health reform had no measurable impact on disparities in 30-day readmissions for MI.
Abstract 9282: The Accumulation of Epicardial Adipose Tissue is an Independent Risk Factor for the Onset of Atrial Fibrillation
Authors: Nakanishi Koki , Fukuda Shota , Shimada Kenei , Otsuka Kenichiro Otsuka , Ehara Shoichi , Matsumoto Kenji , Taguchi Haruyuki , Muro Takeshi , Yoshikawa Junichi , Yoshiyama Minoru
Published: April 2024

Introduction.
Atrial fibrillation (AF) is associated with the structural and electrical remodeling of left atrium (LA) as well as the inflammation. The accumulation of epicardial adipose tissue (EAT) is now recognized as an inflammatory tissue, potentially contributing to the pathogenesis of AF. The developed multi-detector computed tomography (MDCT) is accurate for assessing coronary plaques characteristics as well as additional information for the tissue surrounding the heart, including chamber sizes and EAT volume.

Methods.
This study consisted of 279 patients (176 men, 65 ± 10 years) who had no history of AF. These patients underwent MDCT for the evaluation of coronary artery disease. EAT volume, LA volume, and left ventricular (LV) mass were also measured by MDCT. Patients were divided into 3 groups according to EAT volume (lower tertile; mean 55 ml ranging 21 to 71 ml, middle tertile; mean 87 ml ranging 72 to 100 ml, upper tertile; mean 128 ml ranging 101 to 264 ml). The presence of the onset of AF during follow-up period was confirmed by the findings of electrocardiograms and/or Holter recordings.

Results.
During follow-up of 3.3 ± 1.0 years, AF occurred in 17 (6.1%) patients. Patients with AF were more likely to be older, had significantly higher level of C-reactive protein, and had larger volumes of LV mass, LA and EAT on MDCT. The independent factors for the onset of AF were EAT volume and LA volume index (both p <0.001). The upper tertile of EAT volume had a significant increased risk for the occurrence of AF compared with the lower tertile (p <0.001), and middle tertile (p = 0.03).

Conclusions.
We demonstrated that increased EAT volume, as estimated by MDCT, was independently associated with the occurrence of new onset AF.
Abstract 9306: Site-Specific Reporter Gene Imaging of Stem Cell Transplantation: Early Engraftment Predicts Late Improvement in Cardiac Function
Authors: Narsinh Kazim H , Lan Feng , Liu Junwei , Robbins Robert C , Wu Joseph C
Published: April 2024

Stable genetic modification of cardiac progenitor cells (CPCs) enables quantitative assessment of their engraftment and proliferation using reporter gene imaging. However, random lentiviral integration techniques carry the concomitant risk of introducing inadvertent mutations, including the unacceptable risk of proto-oncogene activation. Here, we demonstrate a safe, clinically applicable method for site-specific PET reporter gene imaging of transplanted CPCs. A triple fusion reporter gene was integrated specifically into chromosome 19 of Sca-1+ human CPCs using the ΦC31 integrase. Targeted integration into this genomic locus was confirmed using nested PCR and Southern blotting. Stably-integrated CPCs (1×10
6
) were then transplanted into ischemic murine myocardium (n=40), and monitored noninvasively using PET, bioluminescence, cardiac MR, and echocardiography for four weeks. hCPC-treated hearts demonstrated a statistically significant improvement in fractional shortening (27.2±2.3% vs. 21.5±1.4%; P=0.04) as well as ejection fraction (48.3±2.6% vs. 42.2±1.7%; P=0.03) at day 14 post-transplant compared to PBS controls, as assessed by echocardiography and cardiac MRI, respectively. Initial PET signal intensity, as a surrogate marker of cellular engraftment, predicted the degree of functional improvement at week 2 (R
2
=0.73) in a “dose-effect” relationship. To investigate the mechanism of hCPC benefit on myocardial function, we isolated the transplanted cells from recipient myocardium by laser capture microdissection and found direct evidence for upregulated expression of the VEGF-α and CTGF pro-angiogenic growth factors in vivo. Here, we demonstrate the first use of site-specific reporter gene imaging to enable prognostic prediction of the ultimate success of CPC therapy. Given the encouraging but variable results of recent cell therapy trials, our results provide valuable insight into the determinants of successful cell therapy.
Abstract 9327: Depletion of Intracellular Ca
2+
Stores Induces Phosphorylation of Stromal Interaction Molecular 1 (STIM1), Which Contributes to the Sustained Phase of Store-operated Ca
2+
Influx in Vascular Endothelial Cells
Authors: Hirano Katsuya , Hanada Akiko , Hirano Mayumi
Published: April 2024

Store-operated Ca
2+
influx (SOC) is a major Ca
2+
entry pathway in vascular endothelial cells, thus contributing to the regulation of endothelial barrier function, nitric oxide production, and angiogenesis. The basic molecular mechanisms underlying SOC have recently been elucidated. Namely, STIM1 serves as a store site Ca
2+
sensor and thereby activates SOC channels. However, the mechanisms regulating SOC remains largely unknown. STIM1 has been previously reported to be a phosphoprotein with unknown function. The present study thus investigated the role of STIM1 phosphorylation in the regulation of SOC. STIM1 phosphorylation was evaluated with a new SDS-PAGE technique utilizing a Phos-tag
TM
compound, which specifically binds to a phosphate group, thus allowing the separation of phosphoproteins from the unphosphorylated form. Thapsigargin, an inhibitor of endoplasmic reticulum Ca
2+
pump, induced a depletion of the Ca
2+
stores in porcine aortic endothelial cells (PAEC) and HeLa cells in the absence of extracellular Ca
2+
. The following repletion of the external Ca
2+
induced a sustained Ca
2+
influx. STIM1 knockdown abolished this influx. Thapsigargin induced >95% phosphorylation of STIM1 in the absence of extracellular Ca
2+
, which persisted irreversibly even after the repletion of external Ca
2+
. Thrombin induced Ca
2+
depletion and subsequent activation of SOC in PAEC, at a lower level than that seen with thapsigargin. Thrombin also induced a lower level of STIM1 phosphorylation in PAEC. However, it returned to the pre-stimulation level after Ca
2+
repletion. Myosin light chain kinase inhibitors, ML-9 and wortmannin, inhibited thapsigargin-induced STIM1 phosphorylation, while Rho kinase inhibitors, Y27632 and H1152, or PKC inhibitor GF109203X had no effect. The effect of the kinase inhibitors were correlated with the effect on the sustained phase of SOC. Analysis of various STIM1 deletion mutants revealed that the C-terminal region is the site of phosphorylation. These results provide the first evidence that STIM1 is phosphorylated following depletion of Ca
2+
stores and this phosphorylation contributes to the maintenance of Ca
2+
influx via SOC. STIM1 phosphorylation may provide a new therapeutic target to maintain normal endothelial functions.
Abstract 9371: Diuretic Use and the Benefit of Cardiac Resynchronization Therapy to Prevent Heart Failure and Death: Secondary Analysis of Data from MADIT-CRT.
Authors: Goldstein Robert E , Haigney Mark C , Krone Ronald J , McNitt Scott A , Moss Arthur J
Published: April 2024

MADIT-CRT demonstrated a reduction in the composite endpoint of heart failure (HF) or death with CRT-D vs. ICD-only therapy in patients with NYHA class I-II, ejection fraction <0.30, and QRS >130ms. Additional predictive variables would aid in selecting patients for preventive CRT-D. We hypothesized that diuretic use at study enrollment might identify patients with more advanced cardiac impairment and incipient HF and thus greater potential for reduction in later overt HF or death with CRT-D. At baseline, 1228 patients were diuretic users and 592 were diuretic non-users. Kaplan-Meier graphs are shown for the two subgroups. Diuretic users showed a relatively high probability of overt HF or death with ICD alone plus a large, highly significant reduction in the risk of this end point with CRT-D therapy. Nonusers had fewer of these events with ICD and modest reduction of borderline statistical significance with CRT-D. As anticipated, the predictive information derived from diuretic use was not unique: when adjusted for imbalances in relevant baseline characteristics (e.g., serum creatinine), diuretic users and non-users experienced similar benefit from CRT-D therapy.

Conclusion:
in MADIT-CRT, the physician's pre-enrollment decision to use diuretics discriminated between a subgroup achieving a strikingly significant benefit from CRT-D therapy and one receiving little likelihood of benefit. This finding may aid in selecting optimal management for patients resembling MADIT-CRT enrollees.
Abstract 9386: ASK2 is a Novel Factor Associated with Salt-Sensitive Hypertension
Authors: Kataoka Keiichiro , Koibuchi Nobutaka , Toyama Kensuke , Sueta Daisuke , Dong Yi-Fei , Ogawa Hisao , Kim-Mitsuyama Shokei
Published: April 2024

Background:
Apoptosis signal-regulating kinase(ASK)1 and ASK2 are MAP3Ks activated by oxidative stress. We have shown that ASK1 has a pivotal role in cardiovascular diseases. ASK2 has been identified as a binding protein for ASK1, and both ASK1 and ASK2 control their respective activities. Cardiovascular phenotypes of ASK2 deficient mice (ASK2KO) have not been reported.

Methods and Results:
We confirmed ASK2 mRNA expression in hearts, aortas, and kidneys utilizing
in situ hybridization
. ASK2KO had different phenotypes from ASK1 deficient mice (ASK1KO); ASK2KO have hypertension with significant cardiac hypertrophy and fibrosis. To further characterize the hypertension of ASK2KO, we implanted telemetry units in mice to monitor 24 h variability of blood pressure (BP) and heart rates. ASK2KO had a circadian rhythm in BP, and the differences in systolic BP between ASK2KO and WT was greater in dark periods than in light periods. There were no differences in locomotor activities or heart rates between ASK2KO and WT. There were no significant differences between ASK2KO and WT in sympathetic nerve activities or in parameters pertaining to the renin-angiotensin system. The ratio of ASK2KO urine Na/K in dark was lower than that in WT, and urine Ca excretion in ASK2KO was greater than in WT, suggesting that ASK2KO have renal tubular dysfunctions. We fed a high-salt diet to ASK2KO to examine salt sensitivity. Telemetry analysis revealed that blood pressure of ASK2KO was increased by high-salt diets; furthermore, high salt diets-induced BP differences between ASK2KO and WT were greater in dark than in light. High salt-induced urine Ca excretion levels were significantly greater in ASK2KO than in WT. Heart weights of ASK2KO were higher than those of WT at 8 days after a high-salt diet. ASK2KO therefore have salt sensitive hypertension with cardiac hypertrophy, and there are significant differences in renal excretion levels of electrolytes between ASK2KO and WT. Hypertension of ASK2KO does not depend upon the presence of ASK1 because ASK2 and ASK1 double deficient mice also have hypertension.

Conclusion:
ASK2 is a novel factor that is involved in the pathogenesis of salt-sensitive hypertension.
Abstract 9393: Prognostic Value of Cardiac Sympathetic Imaging with Metaiodobenzylguanidine for the Prediction of Mortality in Patients with Cardiorenal Syndrome
Authors: Kouzu Hidemichi , Doi Takahiro , Kawamukai Mina , Nishida Junichi , Mochizuki Atsushi , Muranaka Atsuko , Kokubu Nobuaki , Shimoshige Shinya , Yuda Satoshi , Hase Mamoru , Hashimoto Akiyoshi , Nakata Tomoaki , Tsuchihashi Kazufumi , Miura Tetsuji
Published: April 2024

Background:
Augmentation of sympathetic nerve activity (SNA) is one of the underlying pathphysiologies of cardiorenal syndrome (CRS). However, impact of augmented SNA on prognosis in CRS remains unknown.

Objective:
We examined whether change in cardiac SNA detectable by metaiodobenzylguanidine (MIBG) imaging predicts mortality in patients with CRS.

Methods and Results:
Cardiac SNA activity was quantified as heart-to-mediastinum ratio (HMR) of MIBG image in 280 patients (aged 61 ± 16 years, 73% male) with heart failure (26% ischemic etiology) and reduced left ventricular ejection fraction (<50%). Patients with end-stage renal disease were excluded, and those with estimated glomerular filtration rate of <60 ml/min/1.73m
2
were defined as patients with CRS. During 50 ± 35 months of follow-up, cardiac death occurred in 48 patients (83% heart failure, 17% sudden death). Compared with 113 non-CRS patients, 167 CRS patients were older and had higher prevalence of diabetes, lower ejection fraction, lower hemoglobin level and worse 5-year survival rate (87.4% vs. 75.6% p<0.01). In a Cox proportional hazards model, late HMR of <1.57 (hazard ratio for mortality (HR): 6.98; 95% confidence interval (CI) = 3.33-16.52; p<0.01) and 1 mg/dl decrease in hemoglobin level (HR: 1.29; 95% CI =1.08-1.53; p<0.01) had significant predictive values, though CRS alone did not (HR: 1.57; 95% CI=0.81-3.25; p=0.18). Prognosis of CRS patients with late HMR of ≥1.57 was comparable to that of non-CRS patients (Figure 1). In CRS patients with late HMR of <1.57, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) (HR: 0.29; 95% CI=0.12-0.67; p<0.01) and β−blocker (HR: 0.38; 95% CI=0.17-0.82; p=0.01) were associated with better prognosis (Figure 2).

Conclusions:
Assessment of cardiac SNA by MIBG activity can identify high-risk patients among CRS patients. Current ACEI/ARB and β-blocker therapies appear to improve prognosis of those high-risk patients as well.
Abstract 9395: Oxidative Stress Impairs Desensitization of the G-Protein Coupled Receptors (GPCRs) and Increases Vascular Reactivity by Prolonging the Contractile Responses in the Cerebral Arteries After Subarachnoid Hemorrhage
Authors: Kameda Katsuharu , Kikkawa Yuichiro , Hirano Mayumi , Matsuo Satoshi , Sasaki Tomio , Hirano Katsuya
Published: April 2024

Cerebral vasospasm is a critical determinant in the prognosis of subarachnoid hemorrhage (SAH). Increased vascular reactivity plays a key role in cerebral vasospasm. Not only enhanced contraction, but also prolonged contraction are characteristic of cerebral vasospasm. The up-regulation of GPCRs, including thrombin receptor PAR
1
, contributes to enhanced contraction. The present study addressed the hypothesis that changes in the mechanisms regulating the activity of GPCRs contribute to a prolonged vascular reactivity. This study used a rabbit double SAH model. PAR
1
-activating peptide (PAR
1
AP) induced a transient contraction in the control basilar arteries, while it induced an enhanced and sustained contraction in SAH. When sequentially applied, the second stimulation of PAR
1
AP induced 75% of the first response, while it induced an 8% response in the controls. Thrombin induced an enhanced and sustained contraction in SAH. Notably, the thrombin-induced contraction persisted irreversibly even after terminating thrombin stimulation. The responses to angiotensin II, vasopressin, and PGF
2
α
were also enhanced and prolonged to varying degrees after SAH. These observations suggested that, in addition to receptor up-regulation, the mechanism for the desensitization of GPCRs was impaired during SAH. Intrathecal treatment with argatroban, a thrombin inhibitor, prevented the enhancement of the response to PAR
1
agonists in SAH. However, PAR
1
AP still induced a sustained response, the reactivity to the second stimulation was maintained, and thrombin induced an irreversible contraction. Addition of vitamin C or tempol to argatroban restored a transient response, tachyphylactic attenuation, and reversibility of thrombin response. The level of oxidative stress in the brain tissues increased after SAH, and it was normalized by either argatroban or vitamin C. The results suggest that oxidative stress impairs the desensitization of GPCRs, thus prolonging vascular reactivity after SAH. The impaired desensitization significantly influenced the activity of PAR
1
, thereby causing irreversible contraction. Combined thrombin inhibition and anti-oxidative agents is therefore considered to be a novel strategy to normalize vascular reactivity.
Abstract 9413: A Periodontal Pathogen Promotes Neointimal Formation after Arterial Injury Through Toll-Like Receptor-2 Signaling
Authors: Kobayashi Naho , Suzuki Jun-Ichi , Ogawa Masahito , Aoyama Norio , Hirata Yasunobu , Nagai Ryozo , Izumi Yuichi , Isobe Mitsuaki
Published: April 2024

Introduction--
Inflammatory response plays an important role in neointimal formation after an arterial injury. Previous studies demonstrated that periodontal bacteria were detected in atheromatous plaques, however, little is known about the effects of periodontal infection on vascular remodeling after mechanical injury. Toll-like receptors (TLRs) are key receptors of virulence factors of many periodontal bacteria.

Hypothesis--
We assessed the hypothesis that TLR-2 plays a pivotal role in a periodontopathic bacteria-induced neointimal formation after an arterial injury.

Methods--
Each mouse was implanted with a chamber subcutaneously. The chamber was used to inject bacterial infection into the mice. Two weeks after the chamber implantation, femoral arteries were injured and Porphyromonas gingivalis (P.g.), one of the major periodontopathic bacteria, or vehicle was injected once per week into the chamber. Fourteen days after the arterial injury, the murine femoral arteries were obtained for histopathological and immunohistochemical analyses.

Results--
In WT mice, the anti-P.g. IgG antibody level in plasma samples of the P.g.-injected group significantly increased compared to the vehicle injection group (6.5 ± 1.2-fold vs. vehicle injected group, p < 0.05). Histopathological analysis detected that the intima/media thickness ratio (I/M ratio) in the P.g.-injected group (4.54 ± 0.94, n = 11) significantly increased in comparison to the vehicle-injected group (2.31 ± 0.35, n = 11, p < 0.05). Immunohistochemical analysis detected that the P.g.-injected group showed more MCP-1 positive cells (29.0 ± 8.8 cells, n = 5) in the neointimal area compare to the vehicle-injected group (4.6 ± 1.9 cells, n = 5, p < 0.05). It is noteworthy that TLR-2 deficiency negated (1.74 ± 0.36, n = 10) P.g.-induced neointimal formation compared to the WT mice (4.54 ± 0.94, n = 11, p < 0.05). In TLR-2KO mice, I/M ratio in the P.g.-injected group (1.74 ± 0.36, n = 10) was comparable to the vehicle-injected group (1.54 ± 0.37, n = 6).

Conclusions--
These findings demonstrate that infection with P.g. could promote neointimal formation after an arterial injury through TLR-2 signaling.
Abstract 9416: The Impact of Epicardial Fat Volume on Coronary Artery Disease in Symptomatic Patients of Zero Calcium Sore
Authors: Ito Tsuyoshi , Terashima Mitsuyasu , Nasu Kenya , Ehara Mariko , Kinoshita Yoshihisa , Ito Tatsuya , Kimura Masashi , Tanaka Nobuyoshi , Asakura Yasushi , Asakura Keiko , Tsuchikane Etsuo , Suzuki Takahiko
Published: April 2024

Background
Patients without detectable coronary calcium by computed tomography (CT) have a low rate of obstructive coronary disease and good prognosis. However, in some patients with zero coronary calcium score (zero CS), obstructive coronary stenosis exists and fatal cardiovascular events occur, especially among symptomatic patients. Epicardial fat is known to be a rich source of free fatty acid and inflammatory cytokines and epicardial fat volume (EFV) has been suggested as a predictor of coronary artery disease. The aim of our study is to investigate the impact of EFV on coronary artery disease in symptomatic patients with zero CS.

Methods and Results
From June 2009 to April 2011, consecutive 483 symptomatic patients who underwent multislice CT (MSCT) with zero CS were evaluated. EFV was calculated using dedicated software with manual assistance in defining the epicardial contour on CT images. In each patient, obstructive coronary disease (diameter stenosis>50% on MSCT) and CT-derived vulnerable plaque were assessed with 64-slice CT coronary angiography. CT-derived vulnerable plaque was defined as a plaque with positive vessel remodeling (lesion vessel area>proximal reference vessel area) and low CT attenuation (mean CT density value of the plaque<30Hounsfield Units).

In patients with obstructive coronary disease (n=25), EFV was larger (117.8±40.9cm
3
vs 95.9±41.1cm
3
, p<0.01) and diabetes mellitus (DM) was more common(24% vs 6%, p<0.01) than without obstructive coronary disease. In multivariate analysis, EFV (per 10cm
3
) remained the independent predictor for obstructive coronary disease (Odds ratio(OR);1.20, 95% confidence interval (CI)1.09-1.31, p<0.01).

The patients with CT-derived vulnerable plaque (n=20) had larger EFV than without CT-derived vulnerable plaque (136.4±34.2cm
3
vs 95.4±40.8cm
3
, p<0.01). CT-derived vulnerable plaques were more frequently observed in males (70 % vs 44%, p=0.03) and DM patients (25 % vs 6%, p< 0.01). After adjustment for DM and gender, EFV (per 10cm
3
) remained the independent predictor of the presence of CT-derived vulnerable plaque (OR; 1.20, 95%CI; 1.09-1.32, p<0.01).

Conclusions
EFV can be a useful marker of coronary artery disease in symptomatic patients with zero CS.
Abstract 9418: Selective p38 Inhibitor Administered During Ischemia, but Not Reperfusion, Effectively Attenuates Fatal Arrhythmia in Rats with Ischemia/Reperfusion Injury
Authors: Surinkaew Sirirat , Kumphune Sarawut , Chattipakorn Siriporn , Chattipakorn Nipon
Published: April 2024

p38 mitogen-activated protein kinase (p38) has been shown to play an important role in facilitating myocardial infarction process in ischemia/reperfusion (I/R) injury. Inhibition of p38 prior to ischemia has been shown as cardioprotective. However, the benefit of inhibition of p38 after ischemia or during reperfusion is unknown. We tested the hypothesis that inhibition of p38 at different times during I/R can attenuate ventricular fibrillation (VF) incidence and reduce the infarct size.

Methods:
Adult Wistar rats were subject to 30-min left anterior descending coronary artery (LAD) occlusion, followed by 120-min reperfusion. A p38 inhibitor, SB203580, was given intravenously (2-mg/kg) either at 15 minutes before ischemia (pretreatment group), 15 minutes after LAD occlusion (ischemia group), or at onset of reperfusion. Saline was used as a vehicle in each group. Electrocardiogram was recorded and the arrhythmia score was analyzed based on the frequency and duration of arrhythmias detected (1 is lowest and 5 was highest arrhythmia incidence). The infarct size was determined in each heart.

Results:
SB203580
given before LAD occlusion and during ischemia significantly decreased the overall arrhythmia score and the incidence of VT/VF, compared with the vehicle-treated group (Figure). However,
SB203580
given at onset of reperfusion did not show this benefit. The time to VT/VF onset was not changed for
SB203580
treated at any time, compared to the vehicle. Unlike arrhythmia incidence, the infarct size was markedly decreased in
SB203580
-treated rats in all groups.

Conclusion:
Although SB203580 could markedly decrease the infarct size when administered before or after LAD occlusion, as well as during reperfusion, it could only effectively attenuate the fatal arrhythmias when given only prior to LAD occlusion and during ischemia. These findings indicate the crucial role of the timing of p38 inhibition in preventing fatal arrhythmia in an I/R model.
Abstract 9434: A Specific IKK Inhibitor Suppresses Experimental Autoimmune Myocarditis in Rats
Authors: Watanabe Ryo , Suzuki Jun-Ichi , Ogawa Masahito , Muto Susumu , Itai Akiko , Hirata Yasunobu , Nagai Ryozo , Isobe Mitsuaki
Published: April 2024

Introduction:
Nuclear factor-kappa B (NF-κB), which is regulated by the inhibitor NF-κB kinase (IKK), plays a critical role in the development of myocarditis. However, little is known about the role of IKK in its pathophysiology.

Hypothesis:
We assessed the hypothesis that IKK inhibition could attenuate cardiac inflammation in the progression of myocarditis.

Methods:
Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354, 15mg/kg/day, n=6) to EAM rats daily; the drug-free vehicle was used as untreated EAM control (n=7). We analyzed the therapeutic effects of IKK inhibition against EAM using echocardiography and pathological examination. Cytokine expression in the hearts and cell proliferation by myosin restimulation were also analyzed.

Results:
Echocardiogram revealed that the IKK inhibitor improved left ventricular fractional shortening (52.7±4.5%) in comparison to the untreated group (37.3±3.1%, p<0.05). Pathologically, severe myocardial cell infiltration was observed in the untreated EAM group (affected area per whole heart, 55.8±6.1%), while the IKK inhibitor treated group showed to suppress these changes (26.3±4.2%, p<0.05). In the IKK inhibitor treated group, mRNA expression of IFN-gamma (3.9 ±0.7 fold vs. untreated group, p<0.05) and MCP-1 (17.1±0.8 fold vs. untreated group, p<0.05) was significantly suppressed in comparison to the untreated EAM group (IFN-gamma: 14.5±2.7 fold, MCP-1: 51.4±3.9 fold). Moreover, the IKK inhibitor suppressed production of IL-2 and T cell proliferation in a dose dependent manner in vitro.

Conclusion:
In conclusion, the IKK inhibitor ameliorated EAM by suppressing cytokine production and attenuating inflammatory cell infiltration. IKK regulation is a promising treatment of clinical myocarditis.
Abstract 9446: Usefulness of Platelet Retention Assay for Diagnosing Acute Coronary Syndromes and Predicting Clinical Outcome in Patients with Chest Pain and/or Shortness of Breath
Authors: Sano Keita , Sugamata Wataru , Deyama Juntaro , Uematsu Manabu , Fujioka Daisuke , Nakamura Takamitsu , Saito Yukio , Kitta Yoshinobu , Obata Jyn-ei , Kawabata Ken-ichi , Kugiyama Kiyotaka
Published: April 2024

Measurement of platelet retention rate (PRR) using a collagen-coated bead column and whole blood as a sample is a new point-of-care assay that reflects platelet aggregate formation. We have previously reported an equivalency of the PRR assay with PFA-100 and light-transmission aggregometry to assess the platelet function. This assay is very simple, low-cost performance and takes < 5 min for all procedure. We tested the hypothesis that the PRR assay may be useful for early diagnosing acute coronary syndromes (ACS) and predicting clinical outcome in patients with chest pain and/or shortness of breath of uncertain origin.

Methods and Results:
The citrated whole blood (1.5 ml) in a syringe was passed through a column with collagen-coated beads (0.1-0.2 mm diameter) using a syringe pump. The PRR in the column was calculated by difference between platelet counts in the blood samples before and after the passage. As retention rate rises, so does platelet aggregability. The PRR was measured at admission in the 129 consecutive patients who were admitted for chest pain and/or shortness of breath of recent onset (< 24 hrs). Of the enrolled patients, 59 (45%) patients had the discharge diagnosis of ACS, and the remaining 70 patients (55%) had non-ACS. The high PRR (>30%, as determined by ROC analysis) provided 78% of sensitivity and 79% of specificity in identifying ACS patients, and the addition of PRR increased the diagnostic power of troponin T (TropT) and CKMB (AUC; combination with PRR 0.80 and 0.91 vs. without PRR 0.62 and 0.80, respectively, p < 0.01). Cardiac events recurred after discharge in 16 patients (1 cardiac death, 1 non-fatal MI, and 14 coronary revascularization) during 1-year follow-up period. The higher PRR had a significant predictive value of the future events, that was independent of use of anti-platelet medications, TropT, C-reactive protein, brain natriuretic peptide (HR 2.2, 95% CI 1.3-71.9, p < 0.01). The addition of PRR increased the predictive ability of TropT (AUC; combination with PRR: 0.80 vs. without PRR 0.62, p < 0.01).

Conclusions:
In triage of patients with chest pain and/or shortness of breath, the platelet retention rate assay may be useful for fast diagnosis of ACS and early risk stratification along with other conventional biomarkers.
Abstract 9458: Coronary CT Angiography for Re-Adjustment of Pre-Test Probability of Obstructive Coronary Artery Disease
Authors: Fujimoto Shinichiro , Kondo Takeshi , Kodama Takahide , Orihara Tadaaki , Sugiyama Junichi , Kondo Makoto , Endo Akira , Fukazawa Hiroshi , Nagaoka Hideki , Oida Akitsugu , Takase Shinichi , Narula Jagat
Published: April 2024

Backgrounds:
Although various clinical algorithms have been proposed for defining pre-test probability of obstructive coronary artery disease (CAD), including Duke clinical score, these metrics suffer from selection bias of inclusion of predominantly high-risk population suitable for conventional coronary angiography. However, with noninvasive coronary CT angiography (CTA) comparative anatomy may also be available for a larger number of low and intermediate risk subjects, and may allow development of more inclusive algorithms.

Methods:
3468 consecutive patients underwent CTA for suspected CAD (65.3±11.3 years, M:F: 1837:1811); patients with known CAD and those showing poor image quality were excluded from the study. Regression coefficients of age, gender, coronary risk factors including hypertension (HT), diabetes (DM), hyperlipidemia (HL) and smoking, history of cerebral infarction and chest symptoms (typical, atypical, or none) were weighed as predictors for CAD by multivariate analysis using logistic regression analysis against CTA findings. Risk score (K-risk) regarding the pre-test probability of CAD were calculated using each regression coefficients

Results:
Regression coefficients of age, gender, HT, DM, HL, smoking, history of cerebral infarction, chest symptom were 1.222, 0.039, 0.386, 0.768, 0.818, 0.385, 0.587, 0.431, respectively, and constant -6.404. The rate of concordance of K-risk and observation value was 82.8%. Area under curve of K-risk calculated by receiver operating characteristic curve was greater than that of Duke clinical score (0.769 vs 0.734 p=0.003).

Conclusions:
A K-risk score developed by comparison to CTA findings in the real-world population with suspected CAD allows for a superior assessment of pre-test probability of CAD. Further study for precision of it would be needed in a multicenter trial.
Abstract 9479: Histopathological Validation of Optical Coherence Tomography Analysis for Lipid-Rich Plaque and Thin-Cap Fibroatheroma
Authors: Fujii Kenichi , Hao Hiroyuki , Fukunaga Masashi , Nakata Tsuyoshi , Sawada Hisashi , Shibuya Masahiko , Miki Kojiro , Kawasaki Daizo , Masutani Motomaru , Ohyanagi Mitsumasa , Masuyama Tohru
Published: April 2024

Background:
Optical coherence tomography (OCT) is a unique imaging modality capable of characterizing important morphological features of vulnerable plaque. However, the histopathological correlation data is limited. This study sought to assess agreement of lipid-rich plaques (LLP) between an OCT system and histology in coronary autopsy specimens

Methods:
OCT examinations were performed in 52 coronary arteries from 19 autopsy hearts within 6 hours after death. LLP were selected for OCT versus histological comparisons. OCT images of LLP were signal-poor regions with diffuse borders >60° in circumferential extent with fibrous cap thickness <300µm. Thin-cap fibroatheroma (TCFA) was defined as LLP with cap thickness <65µm.

Results:
OCT identified 211 focal plaques. Of those, 40 plaques (19%) were matched with the OCT criteria of LLP and 17 plaques (8%) with TCFA. OCT LLP highly associated with prevalence of large lipid deposition within plaques (85%). However, 41% of those plaques contained areas of extracellular lipid accumulation but no necrotic core and inflammatory cells, which are known as preatheroma (upper images in Figure). False-positive diagnoses of OCT for LLP often contained histological evidence of microcalcification deposition within smooth muscle cells (lower images in Figure), hemosiderin deposition, or organized thrombus. Although the sensitivity for detecting TCFA was 100%, it should be noted that the positive predictive value was only 59%. The positive predictive value of TCFA is increased if intravascular ultrasound is used in addition to OCT for detecting TCFA.

Conclusions:
Atherosclerotic lesions are heterogeneous, and OCT light signals are attenuated not only by the lipid component but also by microcalcification and/or hemosiderin within plaques. OCT cannot detect the inflammatory status of atherosclerotic LLP. In this specific population, OCT has a limitation in detecting vulnerable plaques corresponding histological specimen.
Abstract 9504: The Role of Highly Sensitive Cardiac Troponin T in the Diagnosis of Isolated Diastolic Dysfunction: Comparison with Natriuretic Peptides
Authors: Kusumoto Atsushi , Miyata Masaaki , Kubozono Takuro , Ikeda Yoshiyuki , Shinsato Takuro , Fujita Shoji , Takasaki Kunitsugu , Yuasa Toshinori , Hamasaki Shuichi , Tei Chuwa
Published: April 2024

Introduction:
Isolated diastolic dysfunction is a frequent entity but difficult to diagnose. Natriuretic peptides are used as a possible non-invasive parameter to diagnose isolated diastolic dysfunction. Recently, the highly sensitive cardiac troponin T (hs-TnT) has been developed. However, the significance of hs-TnT measurement in isolated diastolic dysfunction remains uncertain. The purpose of this study is to evaluate the correlation between echoardiographic diastolic function and hs-TnT or natriuretic peptides in patients with heart failure and preserved ejection fraction.

Methods:
Consecutive 196 patients with heart failure, who had a left ventricular ejection fraction ≥50%, were enrolled. Hs-TnT, B-type natriuretic peptide (BNP), and N-terminal pro-BNP (NT-proBNP) levels were measured simultaneously. Diastolic function was evaluated by echocardiography using mean E', which is the average of lateral and septal E'.

Results:
The linear regression analysis demonstrated that mean E' correlated with log hs-TnT (R=-0.423, p<0.0001), log BNP (R=-0.321, p<0.0001), and log NT-proBNP (R=-0.367, p<0.0001). We performed the receiver operating characteristics (ROC) curve analysis to predict the diastolic dysfunction, mean E' <10 cm/sec, by biomarkers (Figure). The area under the ROC curve (AUC) for hs-TnT was 0.80, with the highest discriminating sensitivity and specificity being 0.93 and 0.52, respectively at hs-TnT=0.004 ng/mL. The AUC for BNP was 0.63, with the highest discriminating sensitivity and specificity being 0.58 and 0.68, respectively at BNP=59.4 pg/mL. The AUC for NT-proBNP was 0.69, with the highest discriminating sensitivity and specificity being 0.70 and 0.64, respectively at NT-proBNP=125.4 pg/mL.

Conclusions:
The hs-TnT is better than BNP or NT-proBNP in the diagnosis of isolated diastolic dysfunction. The hs-TnT is suggested to represent minor and ongoing myocardial injury in patients with isolated diastolic dysfunction.
Abstract 9505: Short-Term Statin Therapy Improves Murine Deep Venous Thrombosis Resolution While Reducing Thrombus Inflammation: An i
n vivo
Multi-Targeted Imaging Study
Authors: Kim Jin Won , Thompson Brian , Kessinger Chase W. , Henke Peter K. , McCarthy Jason R. , Lin Charles P. , Jaffer Farouc A.
Published: April 2024

Background:
Improving DVT resolution may limit the development of the post-thrombotic syndrome (PTS). Utilizing confocal intravital fluorescence microscopy (IVFM), we investigated the
in vivo
effects of short-term statin therapy on thrombus burden, permeability, and inflammation in subacute murine DVT.

Methods:
In 24 male C57Bl/6J mice with topical FeCl
3
-induced femoral DVT, atorvastatin (1.14 mg/kg/day, ≈ 80 mg/day/human subject, n=12) or PBS (n=12) was administered on days 1-4 via gavage. On day 3, macrophage-targeted nanoparticles (CLIO-AF555, ex/em 555/565 nm) and an MMP activity sensor (MMPsense680, 680/700 nm) were i.v. injected. On day 4, FITC-dextran (490/520 nm) was injected to define thrombus anatomy and to evaluate thrombus permeability. 30 minutes after FITC-dextran injection, IVFM was performed. The
in vivo
thrombus burden, and average thrombus macrophage, MMP activity, and permeability target-to-background ratio (TBR) in the mid-thrombus zone (z-stack of 40 um thickness) were determined from CLIO, MMPsense and FITC signals. Histopathology and fluorescence microscopy studies were performed.

Results:
Atorvastatin decreased DVT area on IVFM (0.17±0.01 mm
2
vs.
0.20±0.03 mm
2
in PBS animals, p=0.001), and by microscopy (% thrombus area, 42.2±12.6% statin
vs.
71.0±12.7% PBS, p<0.001). Thrombus sections from statin-treated animals showed reduced PAI-1 immunoreactivity (14.8±4.7% positive area
vs.
30.7±5.0% in PBS mice, p=0.022). Notably, statin therapy reduced thrombus inflammation compared to PBS-treated animals (macrophage TBR 1.7±0.2
vs.
3.1±0.3, p=0.001; and MMP activity TBR 1.3±0.1
vs.
1.8±0.2, p=0.021, respectively). Thrombus permeability was similar in the two groups (p=NS). Correlative fluorescence microscopy and immunohistochemistry corroborated the
in vivo
imaging findings.

Conclusions:
Short-term statin therapy in subacute DVT reduces thrombus burden and improves DVT resolution
in vivo
. The observed benefits of statin treatment are linked to its anti-thrombotic properties, and occur in the setting of reduced thrombus inflammation and similar thrombus permeability. Statin therapy may offer a clinically translatable approach to improve DVT resolution and to limit PTS.
Abstract 9520: Dapagliflozin, a Novel Antihyperglycemic Agent that Promotes Urinary Glucose Excretion, Reduces Systolic Blood Pressure in Patients with Type 2 Diabetes Mellitus
Authors: Woo Vincent , Langkilde Anna Maria , Sugg Jennifer , Parikh Shamik
Published: April 2024

Background:
Obesity and hypertension commonly occur in patients with type 2 diabetes mellitus (T2DM). Dapagliflozin (DAPA), a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia in T2DM by increasing urinary glucose excretion leading to osmotic diuresis, caloric loss, and weight loss. Using prospective exploratory analyses from 3 Phase III studies in patients with T2DM, we evaluated whether DAPA also reduces blood pressure (BP).

Methods:
Seated systolic and diastolic BP, heart rate, proportion of patients with measured orthostatic hypotension, and adverse events of hypotension, dehydration or hypovolemia were assessed in each study. Study 1 (
NCT00660907
): randomized to DAPA or glipizide added to open-label metformin; both treatments were up-titrated, based on tolerability and glycemic response, to a maximum of 10 mg/day or 20 mg/day, respectively. Study 2 (
NCT00680745
): randomized to DAPA 2.5, 5, or 10 mg or placebo added to open-label glimepiride. Study 3 (
NCT00673231
): randomized to DAPA 2.5, 5, or 10 mg or placebo added to open-label insulin ± oral antidiabetic agents. Use of anti-hypertensive medication was not controlled in these studies.

Results:
DAPA reduced mean systolic BP, and to a lesser extent diastolic BP (Table), without increasing mean heart rate or proportions of patients experiencing orthostatic hypotension. Adverse events of hypotension, dehydration or hypovolemia were reported in 1.5%, 0.4%, and 1.6% of patients receiving DAPA vs 0.7%, 0%, and 1% receiving glipizide or placebo in studies 1, 2 and 3, respectively. These episodes were of mild or moderate intensity and none led to study discontinuation or hospitalization.

Conclusions:
DAPA modestly reduces systolic BP in patients with T2DM who were mostly receiving treatment for hypertension. Further studies employing controlled antihypertensive therapy are required to validate the BP-lowering effect of dapagliflozin in T2DM patients with hypertension.
Abstract 9522: Hs-CRP, Statin Therapy, and Risks of Atrial Fibrillation: An Exploratory Analysis of the JUPITER Trial
Authors: Peña Jessica M , Ridker Paul M , MacFadyen Jean , Glynn Robert J
Published: April 2024

Objective:
We studied whether high-sensitivity C-reactive protein (hs-CRP) is associated with incident atrial fibrillation (AF) and whether treatment with rosuvastatin is associated with a lower incidence of AF compared with placebo.

Background:
Increasing evidence supports a role for inflammation in promoting AF and statins have anti-inflammatory effects that may be relevant for the prevention of AF. However, studies of statin therapy and incident AF have yielded mixed results and not focused on those with an underlying pro-inflammatory response.

Methods and Results:
The JUPITER trial randomized men and women with LDL-C < 130 mg/dL and hs-CRP ≥ 2 mg/dl to receive either rosuvastatin 20 mg daily or placebo. AF was determined from treatment-blind adverse event reports. Among 17,120 JUPITER participants with no prior history of AF or arrhythmia, each increasing tertile of baseline hs-CRP was associated with a 36% increase in the risk of developing AF( 95% CI 1.16-1.60 p-trend <0.01). Random allocation to rosuvastatin as compared with placebo was associated with a 27 percent reduction in the relative risk of developing AF during the trial period; specifically, AF was reported among 138 participants in the placebo group and 100 in the rosuvastatin group (hazard ratio 0.73, 95% CI 0.56-0.94, p=0.01). This association remained significant after multivariate adjustment (adjusted HR for rosuvastatin 0.72, 95% CI 0.55-0.93, p=0.01) as well as in analyses excluding participants who developed a major cardiovascular event prior to the report of AF (adjusted HR for rosuvastatin 0.74, 95% CI 0.57-0.97, p=0.03).

Conclusions:
Within the JUPITER trial cohort of individuals selected for underlying inflammation, increasing levels of hs-CRP were associated with an increased risk of incident AF and random allocation to rosuvastatin significantly reduced that risk.
Abstract 9543: Targeted Deep Resequencing Identifies Coding Variants in The PEAR1 Gene That Play a Role in Platelet Aggregation in Individuals at High Risk for Coronary Artery Disease
Authors: Mathias Rasika A , Kim Yoonhee , Yanek Lisa , Faraday Nauder , Wilson Alexander F , Becker Diane , Becker Lewis
Published: April 2024

Background:
The Genetic Study of Aspirin Responsiveness (GeneSTAR) is a family-based study, designed to examine genetic determinants of platelet aggregation in African American (AA) and European American (EA) healthy subjects with a family history of CAD. Platelet aggregation is heritable, and a previous genomewide association study (GWAS) detected strong association with a common genetic variant in intron 1 of the platelet endothelial aggregation receptor1 (PEAR1) gene in AA and EA GeneSTAR subjects. To build upon these results, we exploited a sequencing approach to identify additional functional genetic variants in PEAR1 that may also play a role in platelet aggregation.

Methods:
104 subjects (45% male, age = 52.34±13.27) were selected based on the hyper and hypo aggregation across three different platelet agonists (Collagen, Epinephrine, and ADP). A 0.3Mb target including PEAR1 was Sanger sequenced at deCODE Genetics. Variants were annotated for function and novelty. Single-variant tests for association (variant presence/absence vs. hyper/hypo aggregation) were performed using Fisher's Exact Test. Collapsed multi-variant tests for association were performed using the Combined Multivariate Collapsing and the Weighted Sum methods. For these tests, variants were collapsed based on: 1) minor allele frequency (MAF) and 2) predicted function.

Results:
235 variants were identified, and 104 were novel. Sixteen missense variants were observed, ten of which were novel. More rare variants (MAF < 5%) were noted in AAs compared to EAs (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in the AA sample (p=7.9E-5); no association was seen for additional exonic variants. However, collapsed multi-variant tests suggest that exonic variants play a more significant role in the EA sample (p = 0.01 for the collapsed coding variants compared to p = 0.05 for rs12041331).

Conclusions:
Genetic variants in the PEAR1 are determinants of an individual's platelet aggregation response. We confirm that a common intronic variant has the strongest association in African Americans, and show that additional exonic variants play a role in platelet aggregation, particularly in European Americans.