bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9219: Community-Level Cardiovascular Risk Factors Impact Geographic Variation in Cardiovascular Disease Hospitalizations for Women
Authors: Rodriguez Fatima , Johnson Caitlin E , Wang Yun , Foody JoAnne M
Published: April 2024

Background:
Prior work has shown significant geographic variation in cardiovascular (CV) risk factors including metabolic syndrome, obesity, and hypercholesterolemia. However, little is known about how variations in CV risk impact CVD-related hospitalizations.

Methods:
Community-level CV risk factors (hypertension, dyslipidemia, hyperglycemia, and elevated waist circumference) were assessed from community-wide health screenings sponsored by Sister to Sister (STS) from Jan 2008-Jan 2009 in 17 major US cities. Using data from the Healthcare Cost and Utilization Project (HCUP), CVD hospitalizations were identified based on ICD9 codes for myocardial infarction (AMI), congestive heart failure (CHF), and other CVD discharges. We linked STS data with HCUP hospitalizations based on common cities and restricted the analysis to women discharged from hospitals inside the 17 STS cities. Using hierarchical models with city as a random intercept, we assessed the impact of city-specific CV risk factors on between-city variance of AMI, CHF, and other CVD hospitalization rates. Analyses were also adjusted for patient age and clinical comorbidities.

Results:
Our analysis yielded a total of 742,445 all-cause discharges across 70 hospitals inside of 13 linked cities. The mean age of women was 51.8 (SD 21.7) with a range of 15 to 101. The overall (city-specific range) proportion of AMI, CHF, and other CVD hospitalizations were 1.03% (0.75 to 1.49%), 2.32% (1.64 to 3.94%), and 2.85% (1.66% to 4.72%), respectively. After adjusting for city-specific CV risk factors, between-city variation was no longer statistically significant for all targeted conditions (Table).

Conclusion:
We demonstrated that geographic variations in AMI, CHF, and other CVD hospitalizations can be partially explained by community-level CV risk factors. This finding suggests that interventions to reduce CVD should be tailored to the unique risk profile and needs of high-risk communities.
Abstract 9238: Fatty Acids and Sudden Cardiac Death
Authors: Chiuve Stephanie E , Rimm Eric B , Sandhu Roopinder K , Rexrode Kathryn M , Manson JoAnn E , Willett Walter C , Albert Christine M
Published: April 2024

Background:
Although dietary guidelines recommend increasing N-6 polyunsaturated fat (PUFA) intake, there are concerns that N-6 PUFAs may compete with N-3 PUFA metabolism and attenuate health benefits. N-3 PUFAs have antiarrhythmic properties and intake is inversely associated with sudden cardiac death (SCD) risk. Little is known regarding the relation of N-6 PUFAs and SCD risk, despite having similar antiarrhythmic properties in experimental models. Therefore we examined the associations, and the potential interactions, of N-6 and N-3 PUFAs on SCD risk.

Methods:
We followed 91,981 women from the Nurses' Health Study, age 34 to 59 in 1980. Information on diet was obtained via questionnaires every 4 years; other factors were assessed biannually. SCD was defined as death within 1 hour of symptom onset. Relative risks (RR) and 95%CI were estimated by multivariable Cox proportional hazards models.

Results:
We documented 385 cases of SCD through June 2010. Total PUFAs were inversely associated with risk of SCD, and similar associations were seen for N-6 and N-3 PUFAs (Table). For N-6 PUFAs, linoleic acid, but not arachidonic acid, was associated with lower risk of SCD. For N-3 PUFAs, alpha-linolenic acid, but not marine N-3 PUFAs (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]), were inversely associated with risk. When modeled as a % total fat (a measure of dietary fat quality), marine N-3 PUFAs were significantly associated with lower risk (RR quintile 5 v. 1: 0.53; 95%CI: 0.37, 0.74 ). Women in the highest tertile of both N-3 and N-6 PUFA intake had the lowest risk of SCD (RR= 0.58; 95%CI: 0.40, 0.82) compared to women in the lowest tertile for both PUFAs (P, interaction=0.02).

Conclusions:
Higher intake of both N-6 and N-3 PUFAs was associated with lower risk of SCD. N-6 PUFA intake enhances, rather than attenuates, the inverse association between N-3 PUFA intake and SCD. These results support the AHA dietary guidelines to increase N-6 and N-3 PUFAs intake for heart health.
Abstract 9245: Incident Atrial Fibrillation is Associated with an Increased Risk of Sudden Cardiac Death in Hypertensive Patients During Antihypertensive Therapy: The LIFE Study
Authors: Okin Peter M , Wachtell Kristian , Hille Darcy A , Kjeldsen Sverre E , Dahlöf Björn , Devereux Richard B
Published: April 2024

Background:
Incident atrial fibrillation (AF) is associated with an increased risk of mortality in the general population and after myocardial infarction. Prevalent AF is associated with an increased risk of appropriate device therapies for ventricular arrhythmias in patients with ICDs and with a higher rate of sudden cardiac death (SCD) in advanced heart failure patients. However, whether hypertensive patients with incident AF are at higher risk of SCD has not been examined.

Methods and Results:
The predictive value of incident AF for SCD was examined in 8831 hypertensive patients with ECG left ventricular hypertrophy (LVH) with no history of AF, in sinus rhythm on their baseline ECG, who were randomly assigned to losartan- or atenolol-based treatment. During 4.8±0.9 years mean follow-up, new-onset AF occurred in 701 patients (7.9%) and SCD in 151 (1.7%). SCD was significantly more frequent in patients with new AF than in those without (3.6 vs 1.5%, p<0.001). In univariate Cox analyses, new-onset AF, treated as a time-varying covariate, was associated with a subsequent 113% higher risk of SCD (HR 2.13, 95% CI 1.31-3.44, p=0.002). In multivariate Cox analyses adjusting for randomized treatment, age, sex, race, body mass index, diabetes, history of heart failure, myocardial infarction, ischemic heart disease, stroke, peripheral vascular disease, smoking, serum total and HDL cholesterol, creatinine, glucose, urine albumin/creatinine ratio and for incident MI, in-treatment heart rate, diastolic and systolic pressure, Cornell voltage-duration product and Sokolow-Lyon voltage LVH treated as time-varying covariates, incident AF remained associated with a 74% increased risk of SCD (HR 1.74, 95% CI 1.05-2.91, p=0.033).

Conclusions:
The development of new-onset of AF identifies hypertensive patients at increased risk of SCD, independent of the higher prevalence of risk factors in patients with new AF, treatment effects, in-treatment blood pressure and the established predictive value of in-treatment ECG LVH and heart rate for SCD in this population.
Abstract 9347: Comparison of Cardiac Stem Cells and Mesenchymal Stem Cells Transplantation on the Cardiac Electrophysiology in Rat Model of Myocardial Infarction
Authors: Wang Tong , Zheng Shaoxin , Zhou Changqing , Wen Zhuzhi , Weng Yinlun , Huang Hui , Wu Wei , Wang Jingfeng
Published: April 2024

Introduction
Whether transplanted cardiac stem cells (CSCs) and mesenchymal stem cells (MSCs) improved ventricular fibrillation threshold (VFT) similarly and whether severe malignant ventricular arrhythmia is induced in the myocardial infarction (MI) model are still unclear. We sought to compare the effects of the CSCs and MSCs transplantation on the electrophysiological characteristics and VFT.

Hypothesis
CSCs are superior to MSCs in modulating the electrophysiological abnormality and improving the VFT in rat model of MI.

Methods
MI was induced in 30 male Sprague-Dawley rats. Two weeks later, animals were randomized to receive 5×10
6
CSCs or 5×10
6
MSCs labeled with PKH26 in phosphate buffer solution (PBS) or PBS alone injection into the infarcted anterior ventricular free wall. Six weeks after the CSCs or MSCs or PBS injection, electrophysiological characteristics and VFT were measured. Labeled CSCs and MSCs were observed in 5 µm cryostat sections from each harvested heart.

Results
The VFTs were improved in the CSCs group compared with the MSCs group (table 1). Labeled CSCs and MSCs were identified in the infarct zone and infarct marginal zone. Labeled CSCs express Connexin-43 and α-sarcomeric actin, while Labeled MSCs express α-sarcomeric actin in vivo.

Conclusions
CSCs are superior to MSCs in improving the VFT in rats with MI. CSCs and MSCs express markers that suggest muscle phenotypes in vivo, but MSCs rarely express Connexin-43.
Abstract 9360: Dual-Energy X-ray Absorptiometry for Quantification of Visceral Adipose Tissue
Authors: Kaul Sanjiv , Rothney Megan R , Peters Dawn , Wacker Wynn , Shapiro Michael , Ergun David
Published: April 2024

Background:
Obesity is the major risk factor for metabolic syndrome and through it diabetes as well as cardiovascular disease. Visceral fat (VF) rather than subcutaneous fat (SF) is the major predictor of adverse events. Currently the gold standard for measuring VF is abdominal x-ray computed tomography (CT), which exposes patients to significant amounts of radiation and is relatively time-consuming. Dual-energy x-ray absorptio-metry (DXA) can accurately measure body composition with high precision, low x-ray exposure and short scanning time. The purpose of this study was to validate a new method whereby VF can be measured by DXA.

Methods:
We studied124 adult men and women volunteers, aged 18 to 90 years, representing a wide range of BMI values (18.5 to 40 kg/m
2
) who underwent DXA and CT in a fasting state within one hour of each other. The DXA VF algorithm uses measurements of the total abdominal thickness, based on x-ray attenuation, and the width of the SF layer along the lateral extent of the abdomen along with geometric constants to estimate SF in the android region. VF is computed by subtracting SF from the total fat in the android region.

Results:
Our results are depicted in the Figure. The coefficient of determination (r²) for regression of CT on iDXA values was 0.959 for females, 0.949 for males and 0.957 combined. The 95% confidence interval for r was 0.968 to 0.985 for the combined data. The 95% confidence interval for the mean of the differences between CT and iDXA VF volume was -96.0 to - 16.3 cm³. Bland-Altman bias was +67 cm³ for females and +43 cm³ for males. The 95% limits of agreement were -339 to +472 cm³ for females and -379 to +465 cm³ for males. Combined, the bias was +56 cm³ with 95% limits of agreement of -355 to +468 cm³.

Conclusion:
We conclude that DXA can measure VF precisely in both men and women. This simple non-invasive method can therefore be used to measure VF in individual patients and help define cardiovascular risk.
Abstract 9375: Sum Absolute QRST Integral Predicts Low Risk of Ventricular Tachyarrhythmias and Sudden Cardiac Death In MADIT II Study
Authors: Tereshchenko Larisa G , McNitt Scott , Han Lichy , Zareba Wojciech
Published: April 2024

Introduction.
The need to extend risk stratification beyond use of ejection fraction is well recognized. New ECG risk marker, sum absolute QRST integral (SAI QRST) was recently proposed and was shown to be associated with low risk of sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) in patients with structural heart disease and primary prevention implantable cardioverter-defibrillators (ICDs). The objective of this study was to validate predictive value of SAI QRST in analysis of landmark ICD trial MADIT II.

Methods.
Baseline orthogonal ECGs were recorded at rest during sinus rhythm in 750 MADIT II study participants and analyzed by customized Matlab software. Absolute QRST integral was measured as the arithmetic sum of areas under the QRST curve, averaged during a 5-minute epoch. Then the sum magnitude of three orthogonal leads absolute QRST integral (SAI QRST) was calculated. Primary end-point for analysis was sustained VT/VF with appropriate ICD therapies (shock or antitachycardia pacing), or sudden cardiac death.

Results.
During 3.5 years of follow-up, 143 patients experienced sustained VT/VF with appropriate ICD therapies, or died suddenly. In univariate analysis lowest quartile of SAI QRST (< 116 mV*ms) was associated with decreased risk of sustained VT/VF with appropriate ICD therapies or sudden cardiac death (Figure 1). In multivariate analysis after adjustment for blood urea nitrogen and New York Heart Association functional class, low quartile SAI QRST was associated with decreased risk of VT/VF or sudden cardiac death as compared to three higher SAI QRST quartiles (Hazard Ratio 0.64 ; 95% CI 0.42 - 0.99 ; p=0.045).

Conclusion
. In post-myocardial infarction patients with depressed ejection fraction the lowest quartile of SAI QRST is associated with lower risk of sustained ventricular tachyarrhythmias and sudden cardiac death than it is observed in patients with higher SAI QRST values. Further study of SAI QRST is warranted.
Abstract 9403: A Periodontal Pathogen Accelerates the Progression of Abdominal Aortic Aneurysm via Toll-Like Receptor-2 Signaling
Authors: Aoyama Norio , Suzuki Jun-Ichi , Ogawa Masahito , Watanabe Ryo , Izumi Yuichi , Hirata Yasunobu , Nagai Ryozo , Isobe Mitsuaki
Published: April 2024

Introduction--
Abdominal aortic aneurysm (AAA) is a life-threatening disorder. Periodontopathic bacteria have been detected at a high rate in specimens obtained from the aortic walls of AAA patients. It has been shown in an animal study that periodontopathic bacteria induce the progression of AAA. Toll-like receptors (TLRs) are key receptors of virulence factors of many periodontal bacteria.

Hypothesis--
We assessed the hypothesis that TLR plays a fundamental role in periodontopathic bacteria-accelerated AAA progression.

Methods--
AAA was experimentally produced with wild-type mice, TLR-2 deficient mice and TLR-4 deficient mice by the peri-aortic application of 0.25 mol/L CaCl2, while NaCl was used as a control. The mice were injected once per week with live Porphyromonas gingivalis (P.g.), which is a major periodontal pathogen, or vehicle. Four weeks after the application of either CaCl2 or NaCl, the aortic samples were obtained. Histological and immunohistochemical analyses were performed to assess the mechanism of AAA progression.

Results--
P.g.-injected and CaCl2-treated wild-type mice (n = 10) showed a larger increase (1.71 +/− 0.05-fold vs. before operation) than uninfected CaCl2-treated wild-type mice (n = 10) (1.51 +/− 0.09-fold vs. before). Although the aortic diameter of P.g.-injected and CaCl2-treated TLR-4 deficient mice (n = 11) showed a significant increase (1.28 +/− 0.20-fold vs. before, p < 0.05), the aortic diameter of P.g.-injected and CaCl2-treated TLR-2 deficient mice (n = 10) did not increase after the operation (1.07 +/− 0.19-fold vs. before). TLR-2 deficient mice which were injected with P.g. and treated with CaCl2 showed less elastic degradation than wild-type or TLR-4 deficient mice with histological analysis. Immunohistochemical analysis showed that the level of matrix metalloproteinase-2 in the aortic wall of the TLR-2 deficient mice was dramatically lower (1.0 +/− 0.4) than in the wild-type mice (3.0 +/− 0.6, p < 0.05).

Conclusion--
In conclusion, infection with P.g. could accelerate the progression of experimental AAA with TLR-2 signaling.
Abstract 9443: Long-Term Clinical Outcomes of Infarct-Related Artery versus Multivessel Revascularization in Acute ST-Segment Elevation Myocardial Infarction with Multivessel Disease: An Analysis from Korea Acute Myocardial Infarction Registry
Authors: Lee Han Cheol , Choi Jin Hee , Kim Bo Won , Lee Hye Won , Yang Mi Jin , An Sung Gyu , Oh Jun-Hyok , Choi Junghyun , Cha Kwang Soo , Hong Taek Jong
Published: April 2024

Many STEMI patients have multivessel disease. Guidelines recommend multiple revascularization only in cardiogenic shock. We compared clinical outcomes of multivessel revascularization with infarct-related artery(IRA) revascularization in ST-segment myocardial infarction(STEMI) patients.

The 1,283 STEMI patients with multivessel disease[975 in IRA group(group I), 308 in multivessel group(group II)] received primary PCI and were analyzed from a nationwide Korea Acute Myocardial Infarction Registry. Primary outcomes were in-hospital mortality and 12-month major adverse cardiac events(MACE, defined as death, myocardial infarction, and repeated revascularization). Secondary outcomes were in-hospital complications and components of the MACE. There were more hemodynamic unstable patients in group I. In-hospital mortality was higher in group I with marginal significance(6.6% vs. 3.6%, p = 0.051). 12-month MACE occurred in 84(14.6%) in group I, 20(11.5%) in group II(p = 0.294). Each components of MACE were occurred similarly in two groups but non-target vessel revascularization(6.4% vs. 1.7%, p = 0.012). Adjusting for confounding factors, multivessel revascularization did not reduce in-hospital mortality(OR 0.935, 95% CI 0.403-2.167, p=0.875). It was same for 12-month MACE(OR 0.953, 95% CI 0.406-2.233, p = 0.911) and secondary outcomes. But multivessel revascularization reduced non-target vessel revascularization(OR 0.279, 95% CI 0.085-0.922, p = 0.036).

There was no significant difference of clinical outcomes except for low risk of non-target vessel revascularization in multivessel revascularization group. Therefore, results of our study support current guidelines.
Abstract 9466: Recombinant Mitochondrial Transcriptional Factor A Protein Attenuates Pathological Remodeling in Cardiac Myocytes
Authors: Fujino Takeo , Ide Tomomi , Yoshida Masayoshi , Onitsuka Ken , Tanaka Atsushi , Hata Yuko , Takehara Takako , Hosokawa Kazuya , Sakamoto Takafumi , Nishida Motohiro , Sunagawa Kenji
Published: April 2024

Introduction:
Mitochondrial transcriptional factor A (TFAM), a nucleoid protein of mitochondrial DNA (mtDNA), is essential not only for transcription and replication but also maintenance of mtDNA. We have previously reported that, in failing myocardium, TFAM expression and the myocardial mtDNA copy number were decreased. Moreover, in myocardial infarction, overexpression of TFAM attenuated the decrease in the mtDNA copy number, ameliorated cardiac remodeling, and markedly improved survival. Since exogenously-administrated recombinant TFAM protein has been shown to enter mitochondria in cultured cells, we examined our hypothesis that recombinant TFAM protein administration attenuates pathological remodeling in cardiac myocytes.

Methods and Results:
We prepared recombinant human TFAM including mitochondrial targeting signal by glutathione s-transferase fusion protein purification protocol. Recombinant TFAM was successfully recruited into mitochondria of rat neonatal cardiac myocytes, whereas TFAM without mitochondrial targeting signal was observed in nucleus. Treatment with TFAM increased the mtDNA copy number dose-dependently (100 nM: 1.8±0.1-folds), whereas it did not change morphology or population of mitochondria (electron microscopy). To elucidate the mechanism of TFAM on signaling pathways in cardiac hypertrophy, we investigated the effects of TFAM on the nuclear factor of activated T cell (NFAT) signaling, which is a major transcriptional factor regulating pathological hypertrophy and remodeling. TFAM totally abolished NFAT nuclear translocation induced by both angiotensin II (41±3% to 2±1%, p<0.01) and endothelin-1 (43±3% to 3±1%, p<0.01), suppressing respective NFAT transcriptional activity and NFAT-dependent gene expression. TFAM inhibited subsequent morphological hypertrophy of cardiac myocytes (angiotensin II: 1686±37 to 1167±20 μ m
2
, p<0.01, and endothelin-1: 1759±44 to 1206±21 μ m
2
, p<0.01).

Conclusion:
Recombinant TFAM increases the mtDNA copy number, and attenuates angiotensin II and endothelin-1-induced hypertrophy via inhibiting NFAT signaling. Recombinant TFAM would be an attractive, novel therapeutic strategy for cardiac hypertrophy and remodeling.
Abstract 9591: A Novel Quantitative Trait Locus for Coronary Flow
Authors: Ahmed Rizwan , Cook Stuart
Published: April 2024

Background:
Coronary flow (CF) is fundamental for normal cardiac function but the genetic determinants of CF are uncharacterized. We examined the heritability of CF, taking into account blood pressure (BP) effects to discover new Quantitative Trait Loci (QTLs) and candidate genes for CF regulation.

Methods:
We studied in vivo BP and ex vivo CF in normotensive Brown Norway (BN) rat and Spontaneously Hypertensive Rat (SHR), a model of impaired CF, and F1 and F2 progeny of these strains. In vivo BP was measured by carotid artery cannulation in anaesthetized animals. Ex vivo Langendorff perfusion measurements of CF were characterized at baseline, during coronary ligation and following cardiac reperfusion at a controlled heart rate. DNA was extracted and genotyping performed using Illumina's custom 768-plex Goldengate assay.

Results:
1) The broad sense heritability (H2) of CF was 30% at baseline indicating significant and previously unappreciated genetic regulation of CF. 2) CF exhibited no significant correlation with systolic or diastolic BP (baseline: p = 0.18, r = 0.10, n = 172; reperfusion: p = 0.30, r = 0.07, n = 172). 3) Linkage analysis revealed a highly significant CF QTL on rat chromosome 2 (LOD = 5.1), which is the first locus for CF. 4) At the CF locus adenosine monophosphate deaminase 1 (ampd1) and the adenosine A3 receptor (adora3) were identified as candidate genes and are the subject of ongoing studies.

Conclusion:
Our data show that CF is a highly heritable trait and is BP-independent in our experimental model. We identified the first QTL for CF in any species and prioritized candidate genes for CF at the locus. Overall, these data provide the first insights into the genetic control of CF with implications for treatment of conditions characterized by impaired CF.
Abstract 9597: Benefits of Nurse-Guided Cognitive Behavioral Therapy for Depression after Cardiac Surgery
Authors: Doering Lynn V , Chen Belinda , Cross Rebecca , Magsarili Marise , Nyamathi Adey , Irwin Michael R
Published: April 2024

Background:
Depression occurs in 15 to 40% of patients undergoing cardiac surgery, but studies of depression treatment after cardiac surgery have been limited.

Objective:
To evaluate nurse-guided cognitive behavioral therapy (CBT) in a home environment in patients recovering from cardiac surgery.

Methods:
We enrolled 808 cardiac surgery patients from five hospitals. They were screened for depressive symptoms with the Beck Depression Inventory (BDI) in the hospital and one month later and interviewed using the Structured Clinical Interview for DSM-IV (SCID-I); those who met criteria for clinical depression (n=81; 31% female, age 63 ± 9.8 years) were randomized to CBT (n=46) or usual care (UC; n=35). CBT patients received 8 weeks of nurse-guided therapy. UC patients received usual postop care plus biweekly phone calls to maintain contact. After 8 weeks, clinical depression in both groups was re-evaluated. Differences in symptom severity and depression status were determined by McNair-Bowker and Chi-Square tests, respectively. Clinical importance of change in BDI scores was evaluated by the Reliable Change Index method of Jacobson and Traux.

Results:
Intention-to-treat analyses showed greater reduction on the BDI in the CBT group compared to the UC group (mean BDI 9.7 [95% CI, 6.9-12.5] vs 17.6 [95% CI, 14.5-20.6], F=14.7, p<.0001). CBT patients showed greater reduction in symptom severity than did UC patients (Figure). The CBT group was more likely to report remission in clinical depression (63% vs 23%; number need to treat, 2.5 [95% CI, 1.7-4.9]) than the UC group (p<.0001). CBT reduced sleep disturbance (p = .01) and pain interference (, p=.001) and increased perceived control (p = .008).

Conclusions:
Nurse-guided CBT is an effective treatment option for depressed patients after cardiac surgery. Nurse-guided CBT also reduced negative aspects of other common postop complaints and increased patients' sense of control over their cardiac disease.
Abstract 9614: Ca
2+
-Independent Di-phosphorylation of Myosin Light Chain by Rho-associated Coiled-Coil Protein Kinase (ROCK) in the Subjunctional Regions of Cell-Cell Contact Mediates Thrombin-Induced Barrier Dysfunction in Vascular Endothelial Cells
Authors: Hirano Mayumi , Hanada Akiko , Hirano Katsuya
Published: April 2024

A disruption of endothelial barrier function is a predisposing factor for the development of atherosclerosis. The phosphorylation of myosin light chain (MLC) is a key signal of barrier dysfunction. MLC phosphorylation is thought to take place sequentially at S19 and then T18, induces actin stress fiber formation and generates traction force to disrupt cell-cell contact. However, it is unclear how the phosphorylation at two sites contributes to barrier dysfunction. The present study investigated the role of mono- and di-phosphorylation of MLC (MLC-P and MLC-PP) in thrombin-induced barrier dysfunction. Thrombin (1 u/mL) increased the cytosolic Ca
2+
concentration and decreased the transendothelial electrical resistance (TEER) with a peak at 1 and 3-5 min, respectively, in porcine aortic endothelial cells (PAEC). A new SDS-PAGE method using a Phos-tag
TM
compound, which specifically binds to a phosphate group, allowed separate quantification of MLC-P and MLC-PP. PAEC at confluence contained 25% MLC-P and 2% MLC-PP under resting conditions. Thrombin stimulation only slightly increased MLC-P at 3 min, while it showed up on stress fibers. MLC-PP increased to a peak of 35% at 3-5 min, and thereafter declined to the resting level within 15 min. MLC-PP was localized in the subjunctional region of cell-cell contact in addition to the stress fibers at 3 min. ROCK inhibitors, Y27632 and H1152, inhibited the thrombin-induced decrease in TEER, the increase in MLC-PP and the subjunctional localization of MLC-PP, while having no effect on the Ca
2+
response. The MLC-P level remained unaffected by Y27632, while the stress fiber localization was inhibited. Gαq inhibitor, YM254890, inhibited the Ca
2+
response and the decrease in TEER, but it had no effect on the increase in MLC-PP. The introduction of dominant negative mutants of Gα12, Gα13 and Gαq using a cell-penetrating peptide inhibited the thrombin-induced decrease in TEER. The present study provides the first evidence that MLC-P and MLC-PP are differentially regulated in endothelial cells, and that Ca
2+
-independent, ROCK-mediated MLC-PP in the subjunctional regions plays a critical role in the thrombin-induced barrier dysfunction. Inhibition of MLC-PP is thus necessary to restore endothelial barrier dysfunction.
Abstract 9622: Baseline Hemodynamics with Cardiac Performance Response to Contrast Media During Diagnostic Cardiac Catheterization Enhances Prediction of Adverse Events in Heart Failure Patients
Authors: Denardo Scott J , Vock David M , Schmalfuss Carsten M , Young Gregory D , Tcheng James E , Echols Melvin R , Pieper Karen S , O'Connor Christopher M
Published: April 2024

Background.
Anticipating adverse events (death, HF rehospitalization) in heart failure patients (HF pts) could help direct care while reducing event rates and resource utilization. We hypothesized that the combination of baseline pulmonary capillary wedge pressure (PCWP) and change in measures of cardiac performance (ΔCP) following administration of contrast media during diagnostic cardiac catheterization would predict adverse events and add to the predictive value of existing models.

Methods.
Prospective study of 150 consecutive HF pts referred for non-emergency right and left heart catheterization using iodixanol or iopamidol contrast. Hemodynamic variables measured at baseline and following contrast included PCWP and CP (composite of cardiac output, cardiac index and stroke volume, identified from sparse principal component analysis of all hemodynamic variables). Kaplan-Meier curves were generated for 1 year followup using median baseline PCWP and ΔCP to group pts. The effect of adding these hemodynamic parameters to the predictive value of 4 validated risk models (Seattle HF Score; ESCAPE; CHARM; CORONA) was assessed using Cox proportional hazards regression model.

Results.
The average contrast load was 120ml. There was a graded worsening of long-term adverse events, with event rates increasing with the composite metric (Figure). Adding baseline PCWP and ΔCP to the 4 risk models significantly improved their predictive capacity (Table).

Conclusions.
Baseline PCWP with change in CP following administration of contrast predicts adverse events and adds to the predictive value of existing models. The calculations add no cost and can be performed in minutes.
Abstract 9660: Statin-Induced Improvement of Human Endothelial Function Is Mediated by Sphingosine 1-Phosphate
Authors: Sugiura Tomonori , Dohi Yasuaki , Yamashita Sumiyo , Ohte Nobuyuki , Ito Shiori , Mori Chieko , Iwaki Soichiro , Hirowatari Yuji , Ohkawa Ryunosuke , Mishima Yuko , Yatomi Yutaka , Kimura Genjiro , Fujii Satoshi
Published: April 2024

Background:
Endothelium is essential for maintenances of homeostasis in healthy vascular systems. Sphingosine 1-phosphate (S1P) is a potent bioactive lipid responsible for vascular protection through producing nitric oxide, whereas serotonin modulates vascular tone. Recent studies reported that bone marrow derived blood cells play a pivotal role in repairing endothelial damage. This study aimed to examine behavior of serotonin, S1P and their combined effects on endothelial function in vivo and in vitro.

Methods:
Blood was withdrawn from patients without significant cardiovascular risks or medications (n=36, 40±8 years). Plasma serotonin was measured with HPLC. Plasma S1P was measured by HPLC after fluorescent derivatization with o-phthaldialdehyde. Endothelial function was assessed by flow-mediated dilation (FMD). Patients with dyslipidemia (n=14) were subsequently treated with rosuvastatin (2.5mg/day). In vitro, EA.hy926 human vascular endothelial cell line and human peripheral blood mononuclear cell (PBMC)-derived adherent cells, which were confirmed to present endothelial phenotype, were stimulated with S1P (100nmol/L) and endothelial nitric oxide synthase (eNOS) mRNA expression was examined by quantitative real-time PCR.

Results:
Plasma serotonin displayed normal distribution after correction with platelets (serotonin/plt: 23.1±9.8 x10
-9
pmol/platelet). Serotonin/plt inversely correlated with FMD value (3.9±1.7%, r=-0.37, P<0.05) and plasma S1P level (317.5±54.2 nmol/L, r=-0.40, P<0.05). Rosuvastatin improved lipid profiles and increased FMD after 4 weeks. Notably, percent decrease in serotonin/plt was inversely correlated with % increase in S1P (11.6±34.5%, r=-0.55, P<0.05). In vitro, EA.hy926 cells and PBMC-derived adherent cells expressed S1P receptors (S1P
1, 2, 3
) and sphingosine kinases (SphK1, 2). S1P (100 nmol/L), but not serotonin, stimulated eNOS mRNA expression by 1.60±0.61 fold in EA.hy926 cells (n=5) and by 1.81±0.78 fold in PBMC-derived adherent cells (n=5).

Conclusions:
Increased plasma serotonin may mediate vasoconstriction and plasma S1P may provide vasculoprotection against atherogenicity of serotonin. Statin may enhance endothelial function by a novel pathway involving S1P signaling.
Abstract 9724: Impaired Renal Function is Associated with an Increased Risk for Incident Atrial Fibrillation
Authors: Sandhu Roopinder K , Kurth Tobias , Conen David , Cook Nancy R , Ridker Paul M , Albert Christine M
Published: April 2024

Introduction:
The prevalence of atrial fibrillation (AF) and chronic kidney disease (CKD) are rapidly rising. Few prospective studies have explored the association between renal function and risk of incident atrial fibrillation (AF) among an apparently healthy population.

Methods:
A total of 24,746 women participating in the Women's Health Study who were free of cardiovascular disease (CVD), AF and provided a blood sample at baseline were prospectively followed-up for incident AF from 1993-2010. AF was confirmed by medical chart review. Renal function was measured as estimated glomerular filtration rate (eGFR) calculated from baseline creatinine using the Chronic Kidney Disease - Epidemiology (CKD-EPI) equation. Cox models were used to estimate hazard ratios (HR) and 95%CI for incident AF across eGFR categories (<60, 60-74.9, 75-89, and > 90 ml/min/1.73 m
2
) controlling for AF risk factors. In a secondary analysis, eGFR was dichotomized at 60 ml/min/1.73 m
2
based on a GFR definition of chronic kidney disease. Multivariable models controlled for age, systolic blood pressure, body mass index, total cholesterol, C reactive protein concentration, antihypertensive treatment, alcohol, exercise, smoking, diabetes, and postmenopausal hormone use.

Results:
Of the total 24 746 women, 15 374 (62.1%) had an eGFR ≥ 90 ml/min/1.73 m
2
, 5901 (23.8%) had an eGFR 75-89 ml/min/1.73 m
2
, 2463 (10.0%) had an eGFR 60-74 ml/min/1.73 m
2
and 1008 (4.1%) had an eGFR <60 ml/min/1.73 m
2
. During a median 15.4 years of follow-up, 786 incident AF events occurred. The age adjusted incidence rate per 1000 person years across eGFR categories (<60, 60-74.9, 75-89, and > 90 ml/min/1.73 m
2
) was 2.61, 2.01, 2.21, and 2.15. The multivariable-adjusted HR for eGFR categories were 1.36 (95% CI, 1.00-1.84), 0.90 (95% CI, 0.71-1.14), 0.99 (95% CI, 0.84-1.18) and 1.00 (P for trend, 0.48). Among women with eGFR < 60 compared to those with ≥ 60 ml/min/1.73 m
2
, the multivariable adjusted HR was 1.39 (95% CI, 1.04-1.86, p value 0.03).

Conclusions:
In this large prospective cohort of apparently healthy women, we observed no increase in risk of incident AF among women with less severe impairment of renal function. However, there was a significant increase in AF risk observed at a threshold GFR of <60 ml/min/1.73 m
2
.
Abstract 9735: Identification of Phenotypes at Risk of Resistant Hypertension
Authors: Giudice Renata , Izzo Raffaele , De Simone Giovanni , De Marco Marina , Migliore Teresa , Cimmino Claudia S , RAO Maria A , De Luca Nicola , Trimarco Bruno
Published: April 2024

Background:
The presence of elevated blood pressure (BP) despite the use of at least three different medications, including a diuretic, is defined resistant hypertension (RH). RH is associated with high risk of stroke, myocardial infarction and arrhythmia. Detection of high risk phenotypes for RH could be of great help in better addressing and graduating initial therapy. Thus, predictors of RH were identified in a large population of hypertensive patients.

Methods:
We studied 6,215 hypertensive patients (age 53±11 years, 57% men, systolic BP [SBP]: 158±20, diastolic BP [DBP]: 99±10) without prevalent cardiovascular disease and with MDRD-estimated glomerular filtrate ratio (eGFR)>30 mL/mmHg/1.73 m2.

Results:
After a mean follow up time of 61±43 months, 12% of the studied population was classified as RH (n=744). Patients with RH were older (57±10 vs 52±11, p<0.0001), and more often women (p<0.0001). At baseline, patients with follow-up RH were more often diabetics (11% vs 4%), more often had metabolic syndrome (MetS, 23% vs 14%; both p<0.0001), and exhibited higher values of SBP, DBP, BMI, fasting triglycerydes and glucose, LV mass, carotid intima-media thickness (IMT), duration of hypertensive disease, pulse pressure/stroke index (PP/SVi), relative wall thickness and lower values of eGFR and serum potassium (all p<0.001). In a Cox model including the variables that were different in the descriptive analysis, follow up RH was independently predicted by: female sex (p=0.015; HR=1.22; CI=1.04-1.42), older age (p<0.0001; HR=1.03/year: CI=1.02-1.04), higher LV mass index (p=0.001; HR=1.02/g*m-2.7; CI=1.02-1.03) and SBP (p<0.0001; HR=1.05/x 5 mmHg; CI 1.01-1.10), longer duration of hypertension (p<0.0001; HR=1.02/year; CI 1.01-1.03) and MetS (p<0.003; HR=1.36; CI 1.11-1.67), at the initial visit, without a significant impact for diabetes, BMI, smoking habits, DBP, eGFR, serum potassium, fasting triglycerides and glucose, IMT and PP/SVi.

Conclusion:
In essential hypertensive patients, resistance to maximal antihypertensive therapy is more frequent in women with MetS and is predicted by older age, higher initial values of SBP, longer duration of hypertensive disease and presence of cardiovascular target organ damage.
Abstract 9763: Discovery of a New Role of Human Resistin in Hepatocyte Low-Density Lipoprotein (LDL) Receptor Suppression Mediated by PCSK9
Authors: Melone Michelle , Rashid Shirya
Published: April 2024

Background:
Serum levels of the adipose tissue-derived signalling protein, resistin, are increased in human obesity and are positively correlated with atherosclerotic cardiovascular disease (ASCVD). However, the function of resistin in humans has been enigmatic. An elevation in serum low-density lipoprotein (LDL) levels is both necessary and sufficient for ASCVD development in humans. However, few physiological factors have been identified that directly affect LDL levels through its main receptor, the LDL receptor (LDLR). In this study, we wished to determine if human resistin plays a role in regulating the uptake of atherogenic LDL in human hepatocytes.

Methods:
Human hepatocytes (HepG2 and primary) were treated for 24 hours with: (1.) purified human resistin at various concentrations, with and without PCSK9 siRNA, and with and without lovastatin; and (2.) obese human serum with elevated resistin levels or serum from which resistin was removed via antibody-immunoprecipitation. The effect of the treatments on cellular LDL receptor (LDLR) and PCSK9 mRNA and protein levels were determined via real-time PCR and Western blotting, respectively.

Results:
Resistin, at physiological levels observed in human obesity (50 ng/mL), downregulated hepatocyte LDLR expression substantially by 40%. A key mechanism by which human resistin inhibited hepatocyte LDLR was via increased expression of the recently identified protease, PCSK9, which enhances intracellular LDLR lysosomal degradation. To support this notion, we showed that the addition of resistin reversed the marked over 100% elevation in LDLR expression induced with PCSK9 siRNA treatment. The quantitatively important role of human resistin in LDLR expression was demonstrated by antibody-immunoprecipitation removal of resistin in obese human serum, which increased serum stimulation of LDLR markedly by 80%. Furthermore, resistin diminished statin-mediated upregulation of LDLR by 70%, implicating resistin in the relative ineffectiveness of statins in selective target populations.

Conclusions:
These results reveal for the first time that resistin is potentially a highly attractive therapeutic target in ameliorating elevated serum LDL, and, thereby, ASCVD, in obese humans.
Abstract 9770: Anatomic Findings and Myocardial Extensions Into the Thoracic Venous Connections of the Heart
Authors: DeSimone Christopher V , Noheria Amit , Lachman Nirusha , Edwards William D , Gami Apoor S , Talreja Deepak , Friedman Paul A , Munger Thomas M , Hammill Stephen C , Packer Douglas L , Asirvatham Samuel J
Published: April 2024

Introduction:
Cardiac veins serve as substrate for arrhythmogenesis, and are especially involved as foci in atrial fibrillation. Understanding cardiac vein anatomy along with myocardial extension into these structures can improve electrophysiological mapping and electrical isolation of arrhythmogenic substrate. Accurately defining cardiac vein anatomy is critical in improving success of ablation therapy for atrial fibrillation.

Methods:
We performed measurements on 620 formalin-fixed autopsy hearts explanted from October 1998 to July 2003. The integrity of the thoracic veins and their cardiac connections were examined and systematic measurements of the superior and inferior vena cavae, azygous vein, vein of Marshall, coronary sinus, and pulmonary veins were performed and data were analyzed using univariate statistics.

Results:
We found that muscular extensions into the pulmonary veins were visible in 99% of the examined hearts, and were circumferential around the vein ostia (99.6%). Muscle extension into the SVC was found in 78% of examined hearts. These extensions were largely circumferential around the ostium (39%), but were also found to be asymmetric in a majority of hearts. Asymmetry was found in hearts with longer muscle extensions; no symmetry was observed in extensions greater than 0.8cm. Muscle extensions into the IVC were not seen. Occasionally, macroscopic muscle extensions into the azygous vein were visible (6%). The vein of Marshall was found to be patent to probing in the majority of hearts examined (72%) and was almost always overlying the lateral left atrial endocardial ridge.

Conclusions:
Our data suggest that all pulmonary veins need to be electrically isolated during atrial fibrillation ablation because of the almost universal presence of myocardial tissue extending into the veins. Mapping of the SVC should be done circumferentially and if potentials are noted isolation should also be performed. The IVC did not have muscle extensions and is unlikely to be a site of arrhythmogenesis. The azygous vein occasionally had muscle extensions and thus requires mapping and possible isolation. The vein of Marshall can be a substrate for arrhythmogenesis and is accessible for ablation by targeting the lateral left atrial endocardial ridge.
Abstract 9801: Increased High-Mobility Group Box1 Expression at Ruptured Plaque Was Associated with Microvascular Damage after Reperfusion in Patients with Myocardial Infarction
Authors: Kohno Takashi , Anzai Toshihisa , Ohki Takahiro , Itabashi Yuji , Yoshizawa Akihiro , Yoshikawa Tsutomu , Fukuda Keiichi
Published: April 2024

Background:
Locally increased inflammatory response at the ruptured plaque contributes to no-reflow phenomenon. High-mobility group box1 (HMGB1) is a potent innate danger signal released from injured and activated immune cells, that initiates pro-inflammatory response. We hypothesized that culprit coronary artery of ST-elevation myocardial infarction (STEMI) contains an elevated level of HMGB1 that may play an adverse role on myocardial reperfusion.

Methods and Results:
Fifty patients with reperfused STEMI and 35 patients with chronic stable angina (CSA) were examined. Local blood samples from the ruptured plaque were taken in patients with STEMI using aspiration catheterization. Systemic blood samples were taken from the aorta. Local and systemic serum HMGB1 level did not differ between presence or absence of atherosclerotic risk factors, prior use of cardiovascular medications, anterior infarction, collateral, and multivessel disease. Systemic level of HMGB1 was significantly higher in patients with STEMI than in patients with CSA (4.9±2.5 vs. 0.9±1.6 ng/ml, p<0.0001). In patients with STEMI, local serum HMGB1 level at the ruptured plaque was higher compared with systemic level (6.3±4.6 vs. 4.9±2.5 ng/ml, p<0.01). Local HMGB1 level, but not systemic HMGB1 level, was significantly increased in patients with final Thrombolysis In Myocardail Infarction (TIMI) <III (n=7) compared with final TIMI-III (n=43) (9.9±6.3 vs. 5.8±4.1 ng/ml, p<0.05). Among the patients with final TIMI-III, local HMGB1 level was elevated in patients with poor ST-resolution (<50%, n=14) compared with those with good ST-resolution (n=29) (8.2±6.1 vs. 4.8±2.5 ng/ml, p<0.05). Local HMGB1 level was higher in patients with pump failure and ventricular fibrillation/sustained ventricular tachycardia compared with those without (all p<0.05).

Conclusions:
Serum HMGB1 level was increased not only in the systemic circulation, but also at the site of plaque rupture in patients with STEMI. Elevated HMGB1 level at the ruptured plaque was associated with no-reflow phenomenon, poor ST-resolution, and adverse clinical outcomes, suggesting that HMGB1 might be an important factor contributing to the development of microvascular damage after reperfusion in patients with STEMI.
Abstract 9876: Relative Efficacy of Aspirin Therapy in Relation to C-Reactive Protein Levels in Type 2 Diabetic Patients: Subgroup Analysis Derived From the JPAD Trial
Authors: Soejima Hirofumi , Nakayama Masafumi , Morimoto Takeshi , Sakuma Mio , Okada Sadanori , Uemura Shiro , Kanauchi Masao , Doi Naofumi , Jinnouchi Hideaki , Sugiyama Seigo , Waki Masako , Saito Yoshihiko , Ogawa Hisao
Published: April 2024

Background:
The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was undertaken to examine the efficacy of aspirin therapy. It was a multicenter, prospective, randomized, open label, blinded end-point trial conducted from 2002 through 2008 and it had a median follow-up of 4.37 years. Low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein (CRP), prospectively defines the risk of atherosclerotic complications.

Methods:
CRP levels were measured in 1529 patients (772 aspirin therapy patients; and, 757 non-aspirin therapy patients) of the JPAD trial at enrollment. In this subgroup analysis of the JPAD trial, we divided the 1529 patients into either a high CRP group (CRP≥ 0.1 mg /dl) or a low CRP group (CRP< 0.1 mg/dl) according to the baseline CRP levels. We compared the incidence rates of primary cardiovascular events in aspirin users and non-aspirin users, respectively.

Results:
There were no significant differences in the incidence rates of acute myocardial infarction between the High CRP Group and the Low CRP Group (hazard ratio, 1.45; 95% confidence interval, 0.46-6.37; log-rank P=0.5623). The incidence rate of stroke events though was significantly higher in the High CRP Group (44 patients (pts) of 1131) than in the Low CRP Group (7 pts of 398; log-rank P=0.0361, Figure). There was no significant difference in the incidence rates of stroke events between the High CRP Group (20 pts of 562) and the Low CRP Group (5 pts of 210) in the aspirin users, but there was a significant difference between the High CRP Group (24 pts of 569) and the Low CRP Group (2 pts of 188) in the non-aspirin users (Figure).

Conclusions:
Our subgroup analysis of the JPAD trial demonstrates that CRP level predicts the incidence of stroke events in patients with type 2 diabetes mellitus. Aspirin therapy is significantly more effective at preventing stroke events, especially in high CRP patients with type 2 diabetes mellitus.