bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9687: Aldosterone Enhances MR/NADPH Oxidase Physical Association, and Induces Cardiomyocyte Hypertrophy and Cardiac Fibroblast Proliferation via Amplification of IL-18 Signaling
Authors: Valente Anthony J , Chandrasekar Bysani
Published: April 2024

Hyperaldosteronism is associated with inflammation, progressive myocardial hypertrophy, fibrosis and adverse remodeling. Since interleukin (IL)-18 is a hypertrophic and mitogenic inflammatory cytokine, we investigated whether Aldosterone (Aldo)-induced cardiomyocyte (CaM) hypertrophy and cardiac fibroblast (CF) proliferation and migration are IL-18 dependent. Aldo-induced hypertrophy of primary rat CaM was inhibited by the mineralocorticoid receptor (MR) antagonists spiranolactone, and eplerenone. Interestingly, knockdown of IL-18, or its neutralization with IL-18BP or polyclonal anti-rat IgG blunted Aldo’s growth effects. In CaM, Aldo induced IL-18 expression via DPI-inhibitable, Nox2- and Nox4-dependent ROS generation, and NF-κB and AP-1 activation. Knockdown of Nox2, Nox4, p65 or c-Jun inhibited IL-18 and IL-18Rα expression and CaM growth. Further, using GST pull-down assays and co-immunoprecipitation/immunoblotting, we demonstrate for the first time that MR physically associates with Nox2 and Nox4 both in vitro and in vivo under basal conditions, and Aldo enhances their interactions in vivo. In CF, Aldo stimulated DPI-inhibitable, Nox4-dependent ROS generation, IL-18, IL-18Rα, and MMP-9 induction, and IL-18-dependent migration and proliferation. In these cells, MR was found bound to Nox4. Continuous infusion of Aldo into rats resulted in myocardial hypertrophy and fibrosis, DPI-inhibitable ROS generation, MR binding to Nox2 and Nox4, and IL-18, IL-18Rα, and MMP-9 expression in the heart. Co-treatment with spironolactone blunted these effects. Notably, Aldo-induced myocardial hypertrophy and fibrosis were markedly attenuated in IL-18-null mice. These results demonstrate that Aldo amplifies IL-18 signaling in both cell types by inducing IL-18 and its receptor expression. Importantly, Aldo-induced cardiomyocyte hypertrophy and fibroblast proliferation are IL-18 dependent, and may involve the direct interaction of MR with NADPH oxidases. IL-18 is a potential therapeutic target in Aldo-induced myocardial hypertrophy, fibrosis and adverse remodeling.
Abstract 9692: Lower Achieved Systolic Pressure (≤130 mm Hg) is Associated With a Decreased Risk of New Diabetes Mellitus in Hypertensive Patients With Electrocardiographic Left Ventricular Hypertrophy: The LIFE Study
Authors: Okin Peter M , Hille Darcy A , Lindholm Lars H , Kjeldsen Sverre E , Dahlöf Björn , Devereux Richard B
Published: April 2024

Background:
There is a well-established association between higher blood pressure (BP) and insulin resistance and hypertensive patients are at increased risk of developing diabetes mellitus (DM). Although lower achieved systolic BP (SBP) was not associated with reduced mortality or cardiovascular outcomes in diabetic hypertensives or in hypertensive patients with ECG left ventricular hypertrophy (LVH) in the LIFE study, whether more aggressive reduction of SBP is associated with a lower incidence of DM has not been examined.

Methods:
Risk of new-onset DM was examined in relation to last in-treatment SBP prior to DM diagnosis or last in-study measurement in the absence of new DM in 7485 hypertensive patients with ECG LVH with no history of DM randomly assigned to losartan- or atenolol-based treatment. Patients with in-treatment SBP ≤130 mm Hg (lowest quintile at last measurement) and SBP between 131 and 141, were compared with patients with in-treatment SBP ≥142 (median SBP at last measurement).

Results:
During 4.6±1.2 years follow-up, new-onset DM was diagnosed in 520 patients (6.9%). In univariate analyses, compared with in-treatment SBP ≥142, in-treatment SBP ≤130 entered as a time-varying covariate was associated with a 57% lower risk (95% CI 39-69%) of new DM and in-treatment SBP between 131 and 141 with a 30% lower risk (95% CI 14-42%) of developing DM. After adjusting for randomized treatment, age, sex, race, prior antihypertensive therapy, baseline body mass index (BMI), uric acid, serum glucose and baseline HDL cholesterol entered as standard covariates, and for in-treatment Cornell product LVH, diastolic BP, BMI, HDL, hydrochlorothiazide and statin use treated as time-varying covariates, achievement of a SBP ≤130 remained associated with a 38% lower incidence (95% CI 12-57%) of new DM whereas an in-treatment SBP between 131 and 141 was no longer predictive of a reduced risk of new DM.

Conclusions:
Achieved SBP ≤130 is associated with a significantly lower risk of developing new-onset DM in hypertensive patients with ECG LVH, independent of other known and possible risk factors for DM. Further study will be needed to determine whether targeting hypertensive patients without DM to lower SBP goals can reduce the burden of new DM in this high-risk population.
Abstract 97: The Overlap in Frequency Spans of Ventricular Fibrillation and Chest Compression in Cardiac Arrest Patients
Authors: Firoozabadi Reza , Helfenbein Eric , Babaeizadeh Saeed
Published: April 2024

Background
In treating sudden cardiac arrest (SCA) patients, automatic external defibrillators automatically analyze the ECG rhythm to determine if defibrillation is necessary. Currently, this analysis must be done during hands-off period because the electrical artifact induced by chest compression (CC) makes the analysis unreliable. It is desired to analyze the ECG rhythm during CPR to minimize the hands-off period, and hence, improve CPR success. Simple filtering of CC artifact would work only if there is no significant overlap between frequency spans of CC and ventricular fibrillation (VF); otherwise, it would distort the ECG.

Objective
To investigate the overlap between CC and VF frequency spans.

Methods
ECG recordings from 170 SCA adult patients with VF rhythm were used. These cases were a subset of a larger database collected for a clinical study in 6 ambulances in 3 European regions using Laerdal HeartStart 4000 defibrillators. The defibrillator had an extra chest pad with an accelerometer and a pressure sensor to record the CC signal. The VF and CC frequency spans were calculated by frequency-domain analysis of the signals.

Results
The figure below demonstrates the frequency spans of VF and CC in patients with VF rhythm going under CPR. The plots are normalized and also include the higher harmonics. A significant overlap is observed at the range of 80 to 140 compressions-per-minute.

Conclusion
The significant overlap in frequency spans of VF and CC makes it challenging to filter the CC artifact without removing parts of VF information and hence distorting the ECG signal. Therefore, techniques for analyzing ECG during CPR should be smarter than merely filtering the CC artifact.
Abstract 9707: Risk Reclassification of Mortality by Exercise Myocardial Perfusion Imaging
Authors: Koh Angela , Gao Fei , Keng Felix Y , Tan Ru-san , Chua Terrance S
Published: April 2024

Background & Aim:
There is growing interest in net reclassification methods for evaluating incremental value of myocardial perfusion imaging (MPI) over clinical markers in clinical risk stratification. In exercise testing, net reclassification improvement (NRI) analysis has not been used in large patient cohorts. We aim to assess prognostic and net reclassification value of exercise and MPI by single-photon emission computed tomography to estimate mortality.

Methods:
We analyzed a prospective cohort of 11,156 patients referred for MPI between 2006 and 2008 (mean age 59 SD 12 years) with no known coronary disease. Mean follow-up time was 2.5 years with all-cause mortality as the primary outcome. In the first analysis involving 11,156 patients, the effect of MPI result on mortality was determined using Cox regression models. We then applied reclassification methodologies to compare between a clinical model that included age, gender, coronary risk factors, ability to exercise, versus a clinical + MPI model that included summed stress score (SSS) and ejection fraction. 6556 (59%) of patients underwent treadmill exercise testing using the Bruce protocol with computation of the Duke Treadmill Score (DTS). In a second analysis that involved only this subgroup of patients who exercised, we compared the clinical model comprising of age, gender, risk factors, SSS, ejection fraction, with a model that included DTS. All risk-estimates were categorized as <1%, 1-3% and >3% risk of mortality in 4 years.

Results:
Mortality occurred in 491 patients(4.4%). In clinical risk-adjusted models, the ability to exercise significantly estimated all-cause mortality (HR=0.147, 95% CI= 0.114 to 0.191, p<0.001). Cox analysis showed that the addition of exercise improved incremental prognostic information (global chi-square increased from 639.58 to 758.02; p<0.001) and risk prediction (NRI =0.06; 95% CI=0.05 to 0.07, p<0.001). Amongst those who were able to exercise, the NRI by adding DTS was 0.08, 95%CI=0.04 to 0.12 (p<0.001).

Conclusion:
In this large cohort of patients, the ability to exercise and Duke Treadmill Score added modest but significant incremental prognostic and risk prediction value over routine clinical and MPI variables in estimating all-cause mortality.
Abstract 9714: The Impact of Chronic Kidney Disease on Complications and All-Cause Mortality After Implantable Device Replacement or Upgrade: Survival Analyses From the REPLACE Registry
Authors: Mittal Suneet , Chung Mina K , Steinberg Jonathan S , Holcomb Richard , Gleva Marye J , Mitchell Kevin , Poole Jeanne E
Published: April 2024

Background:
Chronic kidney disease (CKD) increases the risk for a variety of arrhythmias and these patients often require cardiac implantable electronic device (CIED) implantation. We sought to assess the impact of CKD on complications and mortality in REPLACE.

Methods:
REPLACE was a
prospective
registry of patients undergoing CIED replacement without or with the intent to add or revise one or more leads. CKD stage was based on the National Kidney Foundation classification: stage 1, normal GFR 90; stage 2, GFR 69-89; stage 3, GFR 30-59; stage 4, GFR 15-29; stage 5, GFR <15 or on renal dialysis. The 6-month complication rate and mortality was determined.

Results:
GFR data were available in 1662 (95%) of 1744 patients; by 6-months of follow-up, 254 (15%) of these patients experienced a complication and 67 (4%) patients died. CKD stage did not significantly impact the likelihood of patients experiencing a complication. Cox multivariate analysis identified 5 predictors of survival: prior admission for heart failure (HR 3.05; 95% CI 1.76-5.26), NYHA class III/IV (HR 1.87; 95% CI: 1.07-3.25), antiarrhythmic drug use (HR 1.80; 95% CI: 1.08-2.98), cerebrovascular disease (HR 1.90; 95% CI: 1.11-3.25), and CKD stage (HR 1.5; 95% CI: 1.12-2.0). Patients with stage I-II CKD had a 2.4% 6-month all-cause mortality. In comparison, the mortality was more than 2-fold higher in stage III patients (5.3%), 3-fold higher in stage IV patients (8.6%), and 6-fold higher in stage V patients (16.0%) (Figure).

Conclusions:
In this prospective registry, CKD was an independent and potent risk factor for mortality. The increase in mortality as a function of CKD stage became evident by the
first month
following the CIED procedure. Importantly, the excess mortality was not driven by procedure-related complications. Future investigation needs to be directed towards identification of the mechanisms of death and methods to reduce mortality in patients with CKD who undergo CIED replacement.
Abstract 9730: Hepatic Apolipoprotein M Overexpression Increased Total Sphingosine 1-phosphate Mass and Ameliorate Insulin Resistance in Diet Induced Obesity Mice
Authors: Kurano Makoto , Tsukamoto Kazuhisa , Ohkawa Ryunosuke , Hara Masumi , Iino Junko , Ikeda Hitoshi , Yatomi Yutaka
Published: April 2024

Backgrounds
: Sphingosine 1-phosphate (S1P) is a vasoprotective lipid mediator that is mainly carried on HDL and albumin in the circulation. Since S1P riding on HDL was recently shown to bind to apolipoprotein M (apoM), which is derived from liver, we analyzed the possible involvement of liver in S1P metabolism. Moreover, while both apoM and S1P have been proposed to be involved in glucose metabolism, we also investigated the modulation of glucose metabolism by the overexpression of apoM in mice liver.

Methods and Results
: Using adenoviruses, we overexpressed apoM in HepG2 cells and mice livers and found that both the medium/plasma and cell/liver S1P contents increased. Among lipoprotein subclasses, S1P contents and ApoM increased mainly in HDL fractions. The incubation of S1P in the conditional medium of apoM-overexpressing HepG2 cells interfered with S1P degradation. Failure of HeLa cells to release S1P extracellularly (despite efficient ApoM production and intracellular S1P production) suggests that liver possesses special machinery for S1P export. Furthermore, adenoviral hepatic overexpression of apoM resulted in increase in the S1P level of plasma but not of blood cells, while combination of hepatic apoM overexpression and intraperitoneal administration of C
17
-sphingosine resulted in the increase in the C
17
-S1P level both in livers and in plasma, but again not in blood cells. Regarding glucose metabolism, we found that hepatic apoM overexpression improved fasting blood glucose (Control 156.2 mg/dL vs ApoM 104.8 mg/dL) and ameliorated insulin resistance in diet induced obesity mice, which were partially inhibited by administering
VPC23019
, an S1P receptor 1 antagonist, but not JTE013, an S1P receptor 2 antagonist, rather with JTE013 insulin resistance tended to be improved more than treated with vehicle.

Conclusions
: These results suggest liver involvement in S1P dynamism through production of apoM, which increases circulating plasma S1P by augmenting the S1P output from livers and modifies extracellular S1P metabolism. Regarding the function of ApoM-S1P, ApoM-S1P might ameliorate insulin resistance depending on S1P receptor 1.
Abstract 9770: Overcoming Persistent Hypertension in Primary Care: Potential Impact of a Proven Strategy of Intensive Blood Pressure Management Within a National Patient Cohort
Authors: Stewart Simon , Carrington Melinda J , Swemmer Carla H , Kurstjens Nicol P , Jennings Garry L ,   VIPER-BP Investigators
Published: April 2024

BACKGROUND:
The Valsartan Intensified Primary carE Reduction of Blood Pressure (VIPER-BP) Study involved > 2000 hypertensive patients with persistently elevated BP managed by > 250 family physicians. It demonstrated that a computer-assisted algorithm to apply intensive pharmacological therapy substantially improved BP levels relative to usual care.

METHODS:
From a national cohort study of 733 family physicians and 532,050 patients during 2005-2010, we identified a sub-set of patients being treated for hypertension but with a BP persistently >140/90mmHg who would theoretically benefit from more structured and intensive management. The potential impact of the VIPER-BP intervention, on a sex and BP-specific basis was therefore applied from trial data.

RESULTS:
Of 51,721 hypertensive individuals with follow-up visits in the national cohort, 24,710 (48%) remained hypertensive after one year. Of these, 7,235 men (66 ± 13 years, BP 155 ± 13/86 ± 11 mmHg) and 7,844 women (71 ± 13 years, BP 156 ± 14/84 ± 12 mmHg) being treated for hypertension were identified. The “pre and post” histograms show the modeled impact of the VIPER-BP intervention on systolic BP. In men post-intervention BP was projected to have fallen to 139 ± 6
/
80 ± 9 mmHg and in women to 141 ± 7
/
77 ± 9mmHg. Overall, this strategy would likely achieve additional BP control (<140/90mmHg) in 3,930 (54%) of men (top) and 4,476 (57%) of women.

CONCLUSIONS:
These data confirm the “real-world” potential for structured and intensive BP management to achieve markedly better BP control in primary care in those with persistent hypertension despite initial pharmacological treatment.
Abstract 9789: Gender is Strongly Associated with the Presence of Atherosclerotic Plaque Hemorrhage and an Effect Modifier in the Relation between Plaque Hemorrhage and Cardiovascular Outcome
Authors: Vrijenhoek Joyce E , den Ruijter Hester M , de Borst Gert Jan , de Kleijn Dominique P , de Vries Jean-Paul P , Vink Aryan , Moll Frans L , Pasterkamp Gerard
Published: April 2024

Background Plaque hemorrhage may lead to accelerated progression of atherosclerotic disease. In patients who undergo carotid or femoral endarterectomy, the presence of local plaque hemorrhage predicts future cardiovascular events in any vascular territory. We assessed the hypothesis that gender has an effect on the prevalence of local plaque hemorrhage and the predictive value of plaque hemorrhage for the occurrence of cardiovascular events. Methods Atherosclerotic plaques from 1008 patients (688 male, 320 female) who underwent carotid endarterectomy were analyzed histologically for the presence of plaque hemorrhage. All patients were followed-up for cardiovascular events (non-fatal stroke, non-fatal myocardial infarction, vascular death, vascular intervention) during 3 years. Results Plaques from male patients showed a significantly higher prevalence of plaque hemorrhage compared to women (75% vs. 61%, p<0.001). After a median follow-up of 2.97 years, 208 events had occurred in males (30%) and 80 in females (25%). In a multivariable Cox proportional hazards model, there was a significant interaction between gender and plaque hemorrhage. Cumulative event rate of males with plaque hemorrhage was 32.3% [95% CI=29.1-37.5] compared to 19.1% [95% CI=12.9-24.8] in males without plaque hemorrhage. In females, this event rate was 23.4% [95% CI=17.1-29.3] versus 25.4% [95% CI=17.0-32.9] respectively. Gender-stratified analysis showed that plaque hemorrhage was a strong predictor for events in males (HR 1.8, [95% CI=1.3-2.7]), but this relationship was completely abolished in females (HR 1.1, [95% CI=0.71-1.8]). Conclusions In conclusion, atherosclerotic carotid plaques obtained from females reveal a lower prevalence of plaque hemorrhage compared with males. Local plaque hemorrhage is a strong predictor for secondary manifestations of cardiovascular disease in males but not in females.
Abstract 9864: Depression Inhibits the Positive Effects of Exercise and Light-to-Moderate Alcohol Consumption on C-Reactive Protein Levels
Authors: Suarez Edward C
Published: April 2024

Introduction:
Light to moderate alcohol consumption and exercise are associated with lower cardiovascular mortality and levels of high sensitivity C-reactive protein (hsCRP), a predictor of cardiovascular risk. In contrast, depression is associated with higher cardiovascular risk and hsCRP. We tested the hypothesis that depression attenuates the positive effects of exercise and alcohol consumption on hsCRP.

Methods:
Data were collected on 225 adult men and women (18-65 yrs, 45% women, 40% minorities). The Beck Depression Inventory (BDI) was administered the same day blood samples were collected for hsCRP. BDI scores > 9 indicated depression. The following was used to classify alcohol consumption: never/former (< 1 drink in past 12-months), infrequently (1-3 drinks/month), occasionally (1-7 drinks/week), and regularly (2 drinks/day). Multivariate models were used to test the interaction effects on log-transformed CRP.

Results:
Depression was noted in 20% of participants. Adjusting for a number of coronary risk factors, depression attenuated the effect of exercise on hsCRP (p = .043). Among those who exercised (n = 184), hsCRP was higher in depressed versus non-depressed subjects (p = .005). No gender differences were noted. Depression also attenuated the effect of alcohol consumption on hsCRP in men but not women (p = .006). Among women who abstained (n = 29), those who were depressed exhibited higher hsCRP compared to non-depressed women (p = .03). Depression did not affect hsCRP in women who drank. In non-depressed men (n = 102), drinkers exhibited lower hsCRP relative to non-drinkers (p < .05). In depressed men (n = 19), however, the positive effect of alcohol consumption was not observed. This was most notable among men who reported occasional and regular alcohol use (n= 55), where depressed men exhibited significantly higher hsCRP than non-depressed men (p = .005).

Conclusions:
Independent of cardiovascular risk factors, current depression inhibits the positive effects of exercise on hsCRP. In men, but not women, depression also attenuates the effect of light-to-moderate alcohol intake on hsCRP. Combined, these data suggest the potential for depression to attenuate the health benefits of cardioprotective factors.
Abstract 9890: First-Year Brain Natriuretic Peptide as a Biomarker after Heart Transplant Predicts Outcome and Severity of Cardiac Allograft Vasculopathy
Authors: Rafiei Matthew , Patel Jignesh , Kittleson Michelle , Shiozaki Ryan , Stern Lily , Azarbal Babak , Czer Lawrence , Esmailian Fardad , Kobashigawa Jon
Published: April 2024

Purpose:
Brain natriuretic peptide (BNP) has been reported to be a biomarker for poor outcome after heart transplant. Elevated BNP levels have been associated with reduced survival and an increase in the development of cardiac allograft vasculopathy (CAV). It has not been established whether high levels of BNP at 1-year post-transplant also correlate with severity of cardiac allograft vasculopathy per the new ISHLT cardiac allograft vasculopathy nomenclature.

Methods:
We evaluated 238 patients who received a heart transplant between 2001-2007. Patients were separated into three groups based on BNP levels at the 1st-year: 157 patients with BNP <100 pg/mL, 56 patients with BNP 100-250 pg/mL, and 25 patients with BNP >250 pg/mL. Study patients were followed for 5 years for endpoints of survival, freedom from cardiac allograft vasculopathy (stenosis 30%), and freedom from non-fatal major adverse cardiac events (NF-MACE: MI, CHF, stroke, and need for angioplasty or pacemaker/ICD) and 1st-year freedom from any-treated rejection.

Results:
Patients with BNP >250 pg/mL at the 1st-year had significantly lower survival, freedom from NF-MACE, and freedom from cardiac allograft vasculopathy compared to the lower groups of BNP. Severity of cardiac allograft vasculopathy was higher in the BNP >250 group compared to the other two groups. Of those patients who developed cardiac allograft vasculopathy, the high BNP group had more patients who developed CAV2 or CAV3 compared to patients with BNP 100-250 and BNP <100 pg/mL (24% vs. 4% vs. 7%, respectively; p=0.01). The high BNP group also had less freedom from any-treated rejection than the other two groups.

Conclusion:
Elevated 1st-year levels of BNP >250 pg/mL appears to be a biomarker for poor outcome and the subsequent development of more severe cardiac allograft vasculopathy. Targeted change in immunosuppression such as switch to proliferation signal inhibitors might be considered for this high risk population.
Abstract 9907: Exposure to Oxidized LDL Converts Early Endothelial Progenitors Into Dendritic/Antigen Presenting Cells
Authors: Vinci Maria Cristina , Polvani Gianluca , Pesce Maurizio
Published: April 2024

Background-
“Early” endothelial progenitor cells (eEPCs) derive from circulating monocytes in the presence of angiogenic factors. While eEPCs number and ability to form angiogenic cell clusters in culture are reduced by risk conditions, changes in their function have not been yet reported.
Specific aims and Results -
In the present work, we assessed whether eEPCs are functionally converted into dendritic cells (DCs) by exposure to oxidized LDL (Ox-LDL), a lipoprotein abundant in atherosclerotic plaques. eEPCs were derived by culturing mononuclear cells (MNCs) purified from buffy-coats of healthy blood donors into EGM-2 medium for 7 days. They were then primed for 3 days with a cytokine cocktail containing GM-CSF and IL4 (10 ng/ml) in 10% FBS containing medium. To promote DCs maturation, primed eEPCs were cultured for 2 further days with OxLDL (100μg/ml) in 1% FBS-containing medium. In these conditions, eEPCs showed a typical DCs morphology, acquired DC-specific markers CD80 and CD83 (both <1% vs. 88.1±3.5 and 30.0±5.8; C vs. Ox-LDL,
P
<.05, t-test, n=5) and underwent a robust upregulation of CD86 (48.6±10.1 vs. 81.9±5.1, C vs. Ox-LDL;
P
< .05, t-test, n=5), another DC-specific antigen. Mixed lymphocyte reaction (MLR) experiments revealed high levels of BrdU incorporation in CD3
+
T-cells mixed in a 10:1 ratio with eEPCs-derived DCs. The percentage of BrdU
+
CD3
+
cells was comparable to that of T-cells cocultured with control CD14
+
cells-derived DCs (44.7±1.7 vs. 43.9±6.7,
P
> .05, t-test, n=3). Analysis of 30 cytokines released in the culture supernatant revealed a substantially overlapping secretome profile in eEPCs-derived and CD14
+
-derived DCs. In addition, they showed an angiogenic “fingerprint”, as witnessed by significantly (
P
< .05, t-test, n=3) higher expression of PDGF-BB (790±185 vs. 192±18, pg/ml), IL-8 (25.5±4.4 vs. 3.4±1.1 ng/ml), bFGF (3.5±0.7 vs. 1.0±0.43 pg/ml) and VEGF (535±19 vs 7.8±1.3 pg/ml), compared with CD14
+
-derived DCs.
Conclusions -
The present data show an unexpected
pro
-inflammatory conversion of human eEPCs in response to a potent "auto-antigen" such as OxLDL. This unravels a possible specific immune modulator role of these cells in patients with risk factors, thus contributing to progression of coronary artery disease.
Abstract 9912: Impact of Blood Pressure Lowering Therapy on Left Atrial Function and the Incidence of Atrial Fibrillation in Elderly Hypertensive Patients: Results from a Prospective Study with Speckle Tracking Echocardiography
Authors: Watanabe Takatomo , Kawasaki Masanori , Tanaka Ryuhei , Ono Koji , Saeki Maki , Yagasaki Hiroto , Minatoguchi Shingo , Miwa Hirotaka , Tokoro Fumitaka , Matsuoka Rieko , Abe Shintaro , Goto Yoshiaki , Kato Takashi , Warita Shunichiro , Kojima Tai , Iwama Makoto , Hirose Takeshi , Kawade Masashi , Noda Toshiyuki , Watanabe Sachiro , Minatoguchi Shinya
Published: April 2024

Background:
The risk of atrial fibrillation (AF) associated with left atrial (LA) remodeling is increasing in elderly patients with hypertension (HTN). We assessed the hypothesis that strict blood pressure (BP) lowering therapy has a beneficial effect on LA structure and function and may decrease the incidence of new-onset AF in elderly patients with HTN.

Methods:
First, we recruited 380 patients ≥65 years old with HTN. Exclusion criteria were secondary HTN, atrial arrhythmias, systolic dysfunction (left ventricular ejection fraction <50%), congestive heart failure or myocardial infarction or stroke within the past six months, moderate to sever valvular disease. We divided 234 subjects ≥65 years old, (75±5 years old) into four groups based on mean office BP achieved over the past two years and followed up for two years: a normotensive group (n=71), a HTN group with good BP control (systolic BP <130 and diastolic BP <80 mmHg, n=72), a HTN group with poor BP control (systolic BP ≥140 or diastolic BP ≥90 mmHg, n=41) and a HTN group with moderate BP control (systolic BP ≥ 130 but <140 and diastolic BP <90 or systolic BP <140 mmHg and diastolic BP <90 but ≥80 mmHg, n=50). LA volume, emptying function (EF), strain and strain rate (SR) were measured by speckle tracking echocardiography at baseline and after two years.

Results:
LA volume, EF, strain and SR in the HTN group with good BP control were better preserved than those parameters in the HTN group with poor BP control at baseline and after two years. The incidence of new-onset AF during two years was significantly higher in the HTN group with poor BP control (hazard ratio: 7.015 (95% CI: 2.433 - 20.22), p<0.001).

Conclusion:
LA structure and function were preserved in the HTN group with good BP control, and this was associated with preserved diastolic function and comparable to normal. Strict BP lowering therapy had a beneficial effect on LA structure and function and should be recommended to prevent new-onset AF even in elderly HTN patients.
Abstract 9927: Helix B Surface Peptide, a Small Non-erythropoietic Molecule Based on the Erythropoietin Structure, Effectively Ameliorates the Progression of Chronic Heart Failure in the Rat Post Myocardial Infarction Model
Authors: Ahmet Ismayil , Tae Hyun-Jin , Brines Michael , Cerami Anthony , Lakatta Edward G , Talan Mark
Published: April 2024

The cardioprotective properties of Erythropoietin (EPO) are well documented in pre-clinical studies. However, due to its erythropoietic and prothrombotic properties, the EPO treatment cannot be used in chronic heart failure (CHF), unless indicated by accompanied anemia. Helix B surface peptide (HBSP), a small peptide synthetized on the basis of EPO molecule (ARA290, Araim Pharmaceutical), does not stimulate erythropoiesis. We have reported similarly strong cardioprotective effects of HBSP and EPO in the rat model of myocardial infarction (MI). In this study, we tested the effect of long-term treatment with HBSP on mortality and cardiac remodeling in post-MI CHF in rats. For the 10 months, starting two weeks after left coronary artery ligation, rats received the i.p. injections of HBSP (60µg/kg; n=33) or saline (n=33) 2 times per week. Compared to saline-treated rats, HBSP treatment significantly reduced mortality (35% vs. 65%; p<0.05). Repeated Echocardiography demonstrated remarkable attenuation of left ventricular (LV) chamber dilatation (EDV: 41% vs. 86%; ESV: 44% vs. 135%; p<0.05), LV functional deterioration (EF: -4% vs. -63%; p<0.05) and MI expansion (3% vs. 38%; p<0.05) in HPSP-treated rats compared to saline-treated rats. Blood hematocrit level measured monthly was not affected by HBSP treatment. An invasive hemodynamic assessment at the end of 10-mo treatment showed better LV systolic function (PRSW: 63±5 vs. 40±4; p<0.05) and Arterio-ventricular coupling (Ea/Ees: 1.2±0.2 vs. 2.7±0.7; p<0.05) in HBSP-treated rats compared to saline-treated rats. Histological analysis revealed less apoptosis (0.6±0.1% vs. 0.9±0.1%; p<0.05), myocardial fibrosis (2.6±0.2% vs. 4.1±0.5%; p<0.05), and myocyte hypertrophy (cell diameter: 31±1µm vs. 37±1µm; p<0.05) in non-infarcted myocardium among HBSP-treated rats compared to saline-treated rats. Results suggest that HBSP could be considered as a safe alternative to EPO for a further clinical testing in the patients with chronic heart failure.
Abstract 9937: The Impact of Wall Thickness and Saccular Geometry on the Computational Wall Stress of Descending Thoracic Aortic Aneurysms
Authors: Shang Eric K , Nathan Derek P , Vigmostad Sarah C , Fairman Ronald M , Gorman Robert C , Gorman Joseph H , Chandran Krishnan B , Jackson Benjamin M
Published: April 2024

OBJECTIVES:
Wall stress calculated using finite element analysis (FEA) has been used to predict rupture risk of aortic aneurysms. Prior models often assume uniform aortic wall thickness and fusiform geometry. We examined the effects on peak wall stress (PWS) of including local wall thickness, intraluminal thrombus (ILT), and calcifications in FEA of descending thoracic aortic aneurysms. We further investigated the differences in PWS between saccular and fusiform aneurysms.

METHODS:
CTAs in patients with descending thoracic aortic aneurysms (n=10 total, 5 fusiform and 5 saccular) were analyzed with custom algorithms. For each patient, a control model was defined with uniform wall thickness. Experimental models added the effects of: variable wall thickness (VWT), ILT, and calcifications. A final, combined model incorporated all features. Commercial FEA software was used to load each model with 120 mmHg pressure and compute Von Mises PWS.

RESULTS:
The mean (n=10) PWS of the control models was 410±111 kPa. The imposition of VWT increased PWS (481±126 kPa, P<0.001) (see Figure). The addition of ILT to VWT (359±86 kPa, p=<0.001) reduced PWS, while the addition of calcifications was not statistically significant (506±126 kPa, P=0.07). The final combined model also reduced PWS (368±88 kPa, P<0.001). Saccular aneurysms had significantly increased stress compared to fusiform aneurysms when normalized by aortic diameter in the control model (104±14 kPa/cm, P=0.04 vs 87±8), but not in the combined model (77±7 kPa/cm vs 67±12, P=0.22).

CONCLUSIONS:
Incorporation of local wall thickness can significantly increase PWS in FEA models of thoracic aortic aneurysms. Incorporating variable wall thickness, ILT, and calcifications significantly impacts computed PWS of thoracic aneurysms; sophisticated models may therefore be more accurate in assessing rupture risk. Saccular aneurysms did not demonstrate a significantly higher normalized wall stress than fusiform aneurysms.
Abstract 9960: Electrocardiographic Intervals and Adverse Outcomes in People with Chronic Kidney Disease: Results from the Chronic Renal Insufficiency Cohort Study
Authors: Arkin Joshua M , Deo Rajat , Yang Peter , Zhang Xiaoming , Soliman Elsayed Z , Townsend Raymond , Shlipak Michael G , Feldman Harold I
Published: April 2024

Background:
Abnormalities in electrocardiographic (ECG) intervals have been associated with death and heart failure. We sought to evaluate whether abnormal ECG intervals are associated with adverse events among people with chronic kidney disease (CKD).

Methods:
We evaluated standard baseline ECGs among 3669 participants from the Chronic Renal Insufficiency Cohort Study (CRIC). The association between each of the ECG intervals (PR, QRS, QT and RR) and death, heart failure and the composite, myocardial infarction (MI), peripheral arterial disease (PAD) or stroke was assessed using Cox proportional hazards models. Multivariate analysis included adjustment for demographics, comorbidities, medications and electrolytes. A sensitivity analysis included an assessment of ECGs among the subgroup without baseline cardiovascular disease (CVD).

Results:
After a mean follow-up duration of 5 years, abnormal ECG intervals were associated with an increased incidence of adverse outcomes (Figure 1). The adjusted risk of death was increased among participants with a QRS>100 milliseconds (msec) (HR 1.53 [95%CI 1.21-1.95]), QTc >440 msec (HR 2.15 [95%CI 1.69- 2.74]) and RR<600msec (HR 4.20 [95%CI 1.68-10.51]) compared to participants with a normal QRS, QTc and RR duration, respectively. Abnormal ECG intervals were also independent risk factors for death and the cardiovascular endpoints after excluding participants with prevalent CVD at baseline.

Conclusion:
Cardiac conduction disease in CKD participants, including the subgroup without a history of CVD, is strongly associated with an increased risk of adverse outcomes including death. Future studies need to evaluate whether ECG variables can be effective measures for risk stratification in this high risk subgroup of the population.
Abstract 9961: Semaphorin-induced Inflammation Contributes to Insulin Resistance in Dietary Obesity
Authors: Shimizu Ippei , Yoshida Yohko , Moriya Junji , Katsuno Taro , Suda Masayoshi , Kobayashi Yoshio , Minamino Tohru
Published: April 2024

Semaphorins and their receptors (plexins) are the axon-guiding molecules that also regulate the development of vascular network during embryogenesis. Semaphorin3E (Sema3E) is one of the class 3 semaphorins, and plexinD1 is its receptor. Our recent work shows that Sema3E is up-regulated by p53 under diabetic conditions and inhibits neoangiogenesis in ischemic tissues. Here we show a novel role for Sema3E in adipose tissue inflammation and insulin resistance in obesity. Expression of Sema3E and plexinD1 was up-regulated in adipose tissue of diet-induced obesity (DIO) model. Inhibition of the Sema3E-plexinD1 axis with genetic models or soluble form of the receptors markedly improved adipose tissue inflammation (infiltration of macrophages) and systemic insulin resistance. Conversely, forced expression of sema3E in adipose tissues provoked inflammation and systemic insulin resistance. Disruption of adipose tissue p53 down-regulated the expression of Sema3E and improved adipose tissue inflammation in DIO model. Migration assay showed that Sema3E promoted infiltration of macrophages, and this effect was inhibited when plexinD1 expression was disrupted in macrophages. These results indicate that Sema3E functions as a chemoattractant for macrophages and p53-induced increase of Sema3E-plexinD1 signals provokes adipose tissue inflammation and systemic insulin resistance in DIO model. Inhibition of the Sema3E-plexinD1 axis will be a new therapeutic target for lifestyle-related diseases including diabetes.
Abstract 9973: Late Revealing ECG abnormalities in Patients With Idiopathic Ventricular Fibrillation and Unknown Cause Ventricular Tachycardia Undergoing Implantable Cardioverter Defibrillator
Authors: Lee Ki Hong , Cho Jeong Gwan , Park Hyung Wook , Yoon Nam Sik , Kim Don Han , Ryu Jong Hyun , Ahn Youngkeun , Jeong Myung Ho , PARK Jong chun , Kang Jung Chaee , Hong Young Joon , Kim Ju Han , Lee Min Goo , Park Keun Ho , Sim Doo Sun , Kim Kye Hoon , Yoon Hyun Ju
Published: April 2024

Backgroud:
Despite of meticulous evaluation to reveal the cause of sudden cardiac death, some patients have been implanted Implantable Cardioverter Defibrillator (ICD) without definitive cause. However, they might have certain electrocardiogram (ECG) abnormalities during follow up.

Methods:
We analyzed 145 patients (55.8±16.6 years old, 95 males) who underwent ICD implantation in single center from January 1999 to March 2012. 43 patients (29.7%) were designated as idiopathic ventricular fibrillation (VF) or unknown cause ventricular tachycardia (VT) without organic nor ECG abnormalities. ECG abnormalities including early repolarization (ER) were analyzed during 3.7±2.4 years median follow-up duration. Appropriate shock and electrophysiologic inducibility of recurrent VF/VT were analyzed in patients with late revealing ECG abnormalities.

Results:
32 patients (77.4%) showed ECG abnormalities during long-term follow-up after ICD implantation. 3 patients (7.0%) revealed Brugada type 2 ECG abnormalities, and 29 patients (67.4%) revealed ER. In patients with ER, 16 patients (37.2%) showed notching J point elevation, whereas 13 patients (30.2%) showed slurred J point elevation. Also 9 patients (20.9%) showed rapidly upsloping ST segment elevation (STE), whereas 20 patients (46.5%) showed horizontal/descending STE. Appropriate shock was dominantly delivered in patients with horizontal/descending STE compared with in patients without horizontal/descending STE (40.4% vs. 17.4%, Odd Ratio [OR] 3.17, 95% Confidence Interval [CI] 0.78-6.86, p=0.09). In patients undergoing electrophysiology before ICD implantation, recurrent VF/VT were significantly induced in patients with horizontal/descending STE compared with upsloping STE (71.4% vs. 25.0%, p=0.035). In subgroup analysis, only patients with inferior leads ER received significantly higher appropriate shock than other leads ER (43.5% vs. 10.0%, p=0.015).

Conclusions:
Considerable patients had ECG abnormalities after ICD implantation, although initial meticulous evlaution did not reveal any structural or ECG abnormalities. Also, Horizontal/descending STE in inferior leads might predict further appropriate ICD shock.
Abstract 9990: Activation of Natural Killer T Cells Ameliorates the Development of Angiotensin II-mediated Abdominal Aortic Aneurysm Formation in Obese
ob/ob
Mice
Authors: Saito Akimichi , Ishimori Naoki , Tokuhara Satoshi , Nozawa Atsushi , Nishikawa Mikito , Tsutsui Hiroyuki
Published: April 2024

Objective:

Abdominal aortic aneurysm (AAA) is strongly associated with common atherosclerotic risk factors such as male gender, age, smoking, hypertension, and dyslipidemia. Its underlying cause has been considered to be atherosclerosis in which chronic inflammation including various pro-inflammatory cytokines within the vasculature is involved. We have demonstrated that natural killer T (NKT) cells, a unique subset of T lymphocytes which recognize glycolipid antigens and secrete a large amount of Th1/Th2 cytokines on activation, have a crucial role in the development of atherosclerosis and its plaque rupture as well as metabolic derangements in obese mice. However, it remains unclear that NKT cells are also involved in the development of AAA.

Methods and Results:

Male obese
ob/ob
mice were administered angiotensin II (AngII, 1000ng/kg/min; n=18) or phosphate buffered saline (PBS; n=10) with osmotic minipumps for 4 weeks. The AngII-administered mice were further divided into 2 groups; α-galactosylceramide (αGC, 0.1 μ g/g body weight intraperitoneal injection; AngII-αGC; n=12), which specifically activates NKT cells, and PBS (AngII-PBS; n=6). The maximal abdominal aortic diameter was significantly greater in AngII-PBS than in PBS (1726±288 vs. 833±69 µm,
p
<0.01). AngII administration significantly enhanced mRNA expression of the activation markers of macrophages, F4/80 and major histocompatibility complex (MHC)-class II, by 2.5-folds and 4.6-folds (
p
<0.05 each), and matrix metalloproteinase-2 (MMP-2) by 5.0-folds (
p
<0.01) in aortic tissues from AngII-PBS mice. αGC injection significantly ameliorated the AngII-mediated increase of aortic diameter in AngII-αGC (1241±257 µm,
p
<0.01 vs. AngII-PBS) without affecting the blood pressure (145±6 vs. 154±5 mmHg,
p
=N.S.).

Conclusions:

AngII induces AAA in obese
ob/ob
mice via activating macrophage infiltration and up-regulation of MMP-2 within the vascular tissues. The activation of NKT cells can ameliorate the development of AAA. Regulation of NKT cell activation may be a novel therapeutic strategy against AAA.
Abstract 18008: Post-Transcriptional Regulation of Adiponectin by Micro-RNA 378 in Human Visceral and Subcutaneous Adipose Tissue
Authors: Ishida Masayoshi , Shimabukuro Michio , Yagi Shusuke , Fukuda Daiju , Soeki Takeshi , Sato Hiromi , Uematsu Etsuko , Izaki Hirofumi , Kanayama Hiro-omi , Sata Masataka
Published: April 2024

Purpose:
MicroRNAs (miR), single-stranded non-protein coding gene products, regulate gene expression through post-transcriptional inhibition, and involved in essential biological processes including obesity and insulin resistance. miR-378/378*, which are encoded by PGC-1β gene and counterbalance the metabolic actions of PGC-1β. We conducted to elucidate the role of miR378 expression in human adiposity and adipose tissue inflammation.

Methods:
Study 1 (clinical study): Pair samples were obtained from subcutaneous (SAT) and visceral adipose tissue (VAT) during elective operation in 71 men and 42 women. MiRNA and adipocytokines levels were determined by qRT-PCR. Study 2 (in vitro study): We quantitated adipocytokine transcription during adipogenesis in 3T3-L1 cells overexpressing mimics or inhibitors of miR378 and assessed post-transcriptional regulation in HEK 293 cells expressing a renilla-luciferase-adiponectin-3’UTR sequence.

Results:
Study 1: The mean size, median and mode of adipocytes were negatively correlated with levels of adipose adiponectin in SAT and in VAT. CD68 was negatively, and TLR4, PPARγ2, PGC-1β, and ESRRG were positively correlated with adipose adiponectin. Study 2: Upon in silico search, we found a putative target site for miRNA378/378* in the 3 prime untranslated region (3’ UTR) of adiponectin gene. Expression levels of miR378 as well as adiponectin, ACSL1, GPAT6, PPARγ2 and PGC1β were increased in 3T3L1 during differentiation. The expression of adiponectin and ESRRG, a PGC-1β partner, were inhibited by miR378 mimics. Luminescence activity in HEK 293 cells expressing a renilla-luciferase-adiponectin-3’UTR sequence was inhibited by overexpressing mimics of miR378 and the decrease was recovered by adding the inhibitors of miR378, indicating that the posttranscriptional activity of adiponectin 3’UTR of was regulated via the miR378 binding site.

Conclusion:
There were depot- and size-dependent variations in adiponectin, miRNA378 and its related genes in SAT and VAT. Roles of miR378 and other possible miRNAs were warranted in adiponectin expression and its post-translational modification, which links to metabolic and cardiovascular abnormalities associated with obesity and insulin resistance.
Abstract 18009: Chronic Spinal Cord Stimulation Preserves Cardiac Sympathetic Responses and Normalizes Noradrenergic Gene Expression in Stellate Ganglion in a Canine Heart Failure Model
Authors: Ardell Jeffrey L , Bond Cherie E , Southerland Elizabeth M , Hoover Donald B , Beaumont Eric
Published: April 2024

Background:
Myocardial infarction (MI) leads to adverse remodeling of the heart and cardiac neuronal hierarchy, both contributing to the development of heart failure (HF). Our previous work demonstrated that thoracic spinal cord stimulation (SCS) improved parasympathetic efferent function and survival in a canine model of HF induced by MI and mitral regurgitation (MR). The objective of this study was to determine whether SCS also had beneficial effects on the sympathetic element of the cardiac neuronal hierarchy.

Methods:
A HF model was created in 15 canines by performing sequential surgeries to generate MI and then MR. SCS electrodes and generators were implanted during the first surgery. Seven of the MI/MR animals received SCS (T1-T5; 20 Hz, 200 μsec, 90% of motor threshold) starting one week after MR induction. Generators were not activated in the sham SCS group (n=8). Canines were anesthetized for terminal experiments to record cardiac responses to stellate ganglion stimulation and then to collect the stellate ganglia for RNA analysis by Q-PCR.

Results:
MI/MR blunted the chronotropic and inotropic responses to stimulation of the right or left stellate ganglia. Treatment with reactive SCS significantly improved functional responses to right or left stellate stimulation. For example, right stellate stimulation evoked the following percent changes in sham SCS vs SCS: Cardiac output, 20.6±3.8 vs 66.2±9.2; LV +dp/dt, 38.3±10.2 vs 112.8±13.1; and LV -dp/dt, 13.8±8.3 vs 72.6±12.1 (P<0.05 for all). RNA analysis of stellate ganglia showed that the sham SCS group had significantly increased expression of tyrosine hydroxylase and vesicular monoamine transporter 2 and decreased expression of α2 adrenergic receptor mRNA compared to the SCS treatment group and an acute control group (n=8).

Conclusion:
Chronic MI/MR results in impaired functional sympathetic control of cardiac function and corresponding molecular changes in the stellate ganglion reflective of excessive and adverse sympathetic activation. Therapeutic SCS ameliorates adverse changes in sympathetic function and gene expression in canines with MI/MR.