bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9570: Advanced Endothelial Dysfunction in Patients with Coexistence of Coronary Artery Disease and Peripheral Artery Disease -Effect of Cilostazol on the Advanced Endothelial Dysfunction-
Authors: Maeda Hirofumi , Sugiyama Seigo , Matsuzawa Yasushi , Ohba Keisuke , Akiyama Eiichi , Matsubara Junichi , Nozaki Toshimitsu , Sumida Hitoshi , Ogawa Hisao , Jinnouchi Hideaki
Published: April 2024

Backgrounds

In patients with coronary artery disease (CAD), coexistence of peripheral arterial disease (PAD) indicates poor cardiovascular prognosis. Endothelial dysfunction plays a crucial role in cardiovascular diseases and reactive hyperemia peripheral arterial tonometry (RH-PAT) can noninvasively examine endothelial function. We hypothesized that advanced endothelial dysfunction might associate with the coexistence of CAD and PAD and we investigated effects of cilostazol on the endothelial dysfunction in diabetic patients with PAD.

Methods
and
Results

We measured RH-PAT index (RHI) and ankle-brachial index (ABI) in consecutive stable patients with coronary risk factors (n=511). CAD was defined by coronary angiography (stenosis≥50%, n=358) and PAD was diagnosed by ABI<0.9, ABI>1.4 with vascular imaging evidence of PAD, previous history of peripheral revascularization, or Fontaine classification≥II (n=73). CAD group (n=358) demonstrated significant lower RHI than non-CAD group (n=153) (RHI: 0.52±0.20 vs. 0.60±0.20, p<0.001). RHI were significantly attenuated in patients with coexistence of CAD and PAD (n=63) compared to CAD patients without PAD (n=295) (RHI: 0.40±0.17 vs. 0.54±0.19, p<0.001). In patients with CAD, univariate logistic regression analysis revealed that age (odd ratio (OR)=1.09, p=0.006), smoking (OR=9.94, p<0.001), body mass index (OR=0.76, p=0.001), high density lipoprotein-cholesterol (OR=0.96, p=0.038), estimated glomerular filtration ratio (OR=0.96, p=0.001), and RHI (per 0.1) (OR=0.57, p<0.001) correlated with the presence of PAD. Multivariate logistic regression analysis demonstrated independent correlation of RHI with the coexistence of PAD in CAD-patients (OR: 0.60, 95% confidence interval 0.451 to 0.798, p<0.001). 12 weeks cilostazol treatment (200mg/day) significantly improved the endothelial dysfunction in diabetic patients with PAD (n=21, age 67±7) (RHI; 0.48±0.11 to 0.68±0.25, p<0.001).

Conclusions:

Advanced endothelial dysfunction is associated with coexistence of PAD in CAD patients and cilostazol ameliorated the endothelial dysfunction in diabetic patients with PAD. Severe impairment of endothelial function might be a key component in the concomitant CAD and PAD.
Abstract 9617: Real Angiogenic Potential of Early or Late Outgrowth Endothelial Progenitor Cells is Rigorously Dependent on the Time of Emergence
Authors: Minami Yoshiyasu , Sahara Makoto , Nakajima Toshiaki , Ikutomi Masayasu , Morita Toshihiro , Yamashita Hiroshi , Hirata Yasunobu , Nagai Ryozo , Sata Masataka
Published: April 2024

Background:
Recent studies have suggested that late outgrowth endothelial progenitor cells (EPCs) emerging from cultured peripheral blood mononuclear cells (PBMNCs) might have higher angiogenic potential than that of classically defined early outgrowth EPCs (EOCs). However, it still remains undetermined which of EPC subpopulations rigorously defined by the time of emergence has the highest therapeutic angiogenic potency.

Methods and Results:
Human PBMNCs freshly isolated were cultured under the endothelial cell conditions. EOCs were defined as the cells attached on culture plates at days 3 to 7, and late outgrowth EPCs were defined as the cells forming clusters with cobble stone appearance at days 10 to 30. In addition, late outgrowth EPCs were newly defined according to the dates of colony emergence as follows: MOC at days 10-16, LOC at days 17-23 and VOC at days 24-30. Flow cytometry analyses revealed that the expression patterns of cell surface antigens relating to hematopoietic/endothelial lineages varied among EPC subpopulations, e.g., EOC: CD31
+
CD34
+
CD14
+
CD105
low
and LOC: CD31
+
CD34
+
CD14
-
CD105
high
. Using
in vitro
assays, we found that LOCs had the highest proliferation and tube formation potentials along with the highest expression of eNOS. Then, each EPC subpopulation was intravenously injected into immunocompromised mice at days 1, 3, 5 and 7 after unilateral hindlimb ischemia surgery (each 1×10
5
cells per time). Four weeks after surgery, the mice in LOC-injected group showed significantly enhanced blood flow recovery (blood flow ratios of ischemic/non ischemic leg: 1.02±0.02 [LOC group] versus 0.60±0.16 to 0.85±0.14 [other groups],
P
<0.05) and augmented capillary collateral formation in ischemic leg. To evaluate how much percentage of CD31
+
endothelial cells (ECs) of generated capillaries were derived from the injected EPCs, the GFP-labeled EPCs were injected into the mice with hindlimb ischemia. The proportions of human EPC-derived ECs among a total of CD31
+
ECs in ischemic muscle were 14.3±2.8% in LOC group and 4.0±1.8% to 9.2±2.3% in other groups (
P
<0.05).

Conclusions:
Late outgrowth EPCs emerging at days 17-23 in
ex vivo
culture of human PBMNCs are superior to other EPC subpopulations as to the therapeutic angiogenic potency.
Abstract 9689: Endothelial Function & Sleep Quality
Authors: Behl Muskaan , Veledar Emir , Bliwise Donald , Cunningham Lynn , Vazquez Jennifer , Brigham Kenneth , Quyyumi Arshed
Published: April 2024

Background:
Sleep apnea is associated with cardiovascular disease (CVD). Although obstructive sleep apnea is also associated with abnormal endothelial function (EF), a precursor of CVD, it is unknown whether milder sleep disturbance affects EF. We investigated the relationship between sleep quality and EF, with the hypothesis that poor sleep quality, in the absence of sleep apnea, will be associated with endothelial dysfunction.

Methods:
684 community participants free of CVD, 68% female, aged 37 to 60 years, were enrolled in the Emory-Georgia Tech Predictive Health Institute study. We measured CVD risk factors, sleep quality using the Epworth Sleepiness Scale (ESS) and selected questions from the Pittsburgh Sleep Quality Index (PSQI). EF was measured using brachial artery flow-mediated dilation (FMD). Multivariate analysis of covariance was used to adjust for age, race, gender, smoking, hypertension, diabetes, and body mass index.

Results:
Lower FMD measurements were correlated with higher ESS scores that reflect poor sleep quality (r = -0.0858, p = 0.03), a difference that remained significant after multivariate adjustment for the aforementioned risk factors (β = -0.0009, p = 0.03). Participants who reported cough or snoring during sleep in their PSQI questionnaire also tended to have lower FMD (6.2±3.4% compared to 6.9±4.3%, p = 0.056), a difference that remained significant after multivariate adjustment for risk factors above (p = 0.03).

Conclusion:
In a community-based population without clinically diagnosed sleep apnea, we demonstrate a significant association between sleep quality assessed by questionnaires and EF. Poor sleep quality reflected by symptoms of cough / snoring, or a high ESS score, may contribute to CVD and hypertension by adversely affecting EF.
Abstract 9709: CaMKII-mediated Aberrant Ca2+ Release May Play a Key Role in hte Arrhythmogenesis In Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy
Authors: Okuda Shinichi , Fukuda Masakazu , Suetomi Takeshi , HIno Akihiro , Kato Takayoshi , Doi Masahiro , Kobayashi Shigeki , Yamamoto Takeshi , Matsuzaki Masunori , Yano Masafumi
Published: April 2024

Backgrounds:
Cardiac troponin T (cTnT) mutations causes Familial Hypertrophic Cardiomyopathy (FHC), which leads to sudden cardiac death. In many of the non-dilated forms of FHC-linked cTnT mutations, Ca2+ sensitivity in myofilament is increased. However, the underlying mechanism by which the cTnT mutations leads to lethal arrhythmia remains elusive. Here, we hypothesized that aberrant Ca2+ release via the cardiac ryanodine receptor (RyR2) would occur in FHC. To verify this hypothesis, we investigated local Ca2+ release property in transgenic (TG) mouse model with FHC-related cTnT mutation (delta160E).

Methods and results:
In the TG mouse model, there was no appreciable difference in the structural or functional features of the hearts between wild-type (WT) and TG mice in 6th month of age. In response to isoproterenol (ISO; 10 nmol/L), the Ca2+ spark frequency (SpF: s-1•100µm-1; by fluo4) was much higher in TG cardiomyocytes than in WT cardiomyocytes TG (n=10): 7.8±0.9; WT (n=5): 3.6±0.4; p<0.01. It was largely reversed by CaMKII inhibitor (KN-93 ;1 µM), TG with KN-93(n=5: 5.0±0.3; p<0.05), but not by PKA inhibitor (H-89; 1 µM), TG with H-89(n=5: 7.6±0.3; n.s). In ISO-treated TG cardiomyocytes, time from peak to 70% decline of Ca2+ transient was attenuated by KN-93 (1 µM, n=5: 6.44±0.35 x10-2sec; p<0.05 vs ISO-treated TG (n=5: 7.61±0.18 x10-2sec;), but not by H-89 (1 µM, n=5: 6.88±1.15 x10-2sec; n.s.). ISO-treated TG cardiomyocytes (but not ISO-treated WT: 0/14; n=14) showed spontaneous Ca2+ transient (sCaT) after 5 Hz pacing (12/18; n=13). The spontaneous Ca2+ transient was again attenuated by KN-93 (0/5; n=5), but not by H-89 (3/5; n=5). Moreover, all of these abnormal events in ISO-treated TG cardiomyocytes (i.e. increase in SpF and appearance of sCaT) were reproduced by adding EGTA-AM into ISO-treated WT cardiomyocytes, suggesting that increased Ca2+ buffering capacity, causing an increase in diastolic [Ca2+], predisposes to aberrant Ca2+ release events.

Conclusions:
In FHC-linked cTnT mutated hearts aberrant local Ca2+ release is induced by beta-adrenergic stimulation, presumably due to mutation-linked, increased Ca2+ buffering capacity, and subsequent CaMKII activation.
Abstract 9754: Low Diastolic Arterial Pressure During Pre-Explant Off-Pump Trials can Induce Misleading Overestimation of Left Ventricular Function with Potential Risk for Early Recurrence of Heart Failure after Left Ventricular Assist Device Removal
Authors: Dandel Michael , Potapov Evgenij , Vierecke Juliane , Stepanenko Alexander , Krabatsch Thomas , Knosalla Christoph , Hetzer Roland
Published: April 2024

Background
A major goal after left ventricular assist device (LVAD) implantation is the detection of myocardial recovery which allows LVAD removal. After normalization of LV size, the pre-explant off-pump LVEF is paramount for selection of patients with the potential to remain stable after LVAD removal. However, patients with similar off-pump LVEF but different systemic arterial pressure during off-pump trials often show differences in post-explant cardiac stability. We assessed the importance of diastolic pressure for weaning decisions.

Methods
Among the 82 patients weaned from LVADs since 1995, we selected for evaluation a more homogenous patient cohort which included only those with idiopathic dilated cardiomyopathy before LVAD insertion and pre-explant off-pump LVEF ≥ 45%. We analyzed the relationship between post-weaning stability and pre-explant LV size, geometry and function (end-diastolic diameter, relative wall thickness and short/long axis ratio, systolic wall motion velocity and LVEF), considering also the arterial pressure during off-pump trials.

Results
Pre-explant LVEF in the evaluated patients was 49 ±3.9%. There were no significant differences in pre-explant LVEF between patients with and without heart failure (HF) recurrence during the first 5 post-weaning years (48.5 ±2% vs. 49.2 ±4.3%), but patients with HF recurrence had lower diastolic arterial pressure during the final pre-explant off-pump trial in comparison with post-weaning stable patients. (47.9 ±3.6mmHg vs. 66.9 ±7.8mmHg, p<0.001). Pre-explant off-pump LVEF < 55% with low diastolic arterial pressure of ≤ 50mmHg showed 87.5% predictive value for post-weaning HF recurrence. After maximum unloading promoted cardiac improvement, patients with off-pump arterial diastolic pressure ≤ 50mmHg showed higher pre-explant alterations for all off-pump parameters related to LV size, geometry and function than patients who had off-pump arterial diastolic pressure > 50mmHg (p < 0.05).

Conclusion
Reduced LV afterload in patients with low off-pump diastolic arterial pressure can induce misleading overestimation of LV function. In patients with pre-explant LVEF ≥ 45%, off-pump diastolic arterial pressure ≤ 50mmHg is a relevant risk factor for post-weaning HF recurrence.
Abstract 9761: Survival Benefit of Orally Administered Telmisartan in Hypertensive Rats is NOT a Class Effect of Angiotensin II type 1 Receptor Blockers
Authors: Kishi Takuya , Hirooka Yoshitaka , Sunagawa Kenji
Published: April 2024

[Backgrounds] Previous studies have suggested that abnormal sympathoexcitation worsen the prognosis of hypertensive heart disease. We have demonstrated, in animal models of hypertension, that brain angiotensin II type 1 receptor (AT1R) induces reactive oxygen species (ROS) and ROS causes sympathoexcitation. We also have demonstrated that orally administered AT1R blocker (ARB) telmisartan, not candesartan, reduces the brain ROS and causes sympathoinhibition via blockade of brain AT1R, despite their similar depressor effects. Previous clinical trials have demonstrated that ARBs have beneficial effects in patients with hypertensive. However, it is not clarified whether the benefits are class-effects or not. The aim of the present study was to determine whether orally administered telmisartan improves survival rate of severely hypertensive rats and whether the benefits were class effects of ARBs or not. [Methods and Results] Angiotensin II-infused (100 ng/kg/day) and salt-loaded (8% NaCl diet) stroke-prone spontaneously hypertensive rats (SHRSP) were divided into telmisartan-treated (TLM), candesartan-treated (CND), and control groups. At 5 weeks after the treatment, both telmisartan and candesartan comparably lowered systolic blood pressure (122±14 mmHg vs. 124±9 mmHg, p=ns) and increased survival rate relative to the control (100%, 100%, and 70%, respectively, n=20 for each). However, brain ROS and urinary norepinephrine excretion (uNE: a marker of sympathoexcitation) were significantly lower in TLM than in CND (brain ROS: 0.8±0.1 μmol/g vs. 1.1±0.1 μmol/g, p<0.01 and uNE: 1.1±0.2 μg/day vs. 1.5±0.2 μg/day, n=20 for each, p<0.05). At 7 weeks, the survival rate was higher in TLM than CND (85% vs. 60%). At 9 weeks no rats survived in CND, whereas 40% survived in TLM. Heart/body weight, left ventricular (LV) end-systolic dimension, and LV wall thickness were significantly lower in TLM than in CND (Heart/body weight; 2.8±0.2 mg/g vs. 3.5±0.1 mg/g, n= 12 and 20, p<0.05). [Conclusion] Orally administered telmisartan prevents LV hypertrophy, preserves LV function and markedly improves survival rate of severely hypertensive rats associated with sympathoinhibition via antioxidant in the brain. These benefits of TLM are not class effects of ARBs.
Abstract 9773: Phage Display of
D
esigned
A
nkyrin
R
epeat
P
roteins (DARPins) against the I Domain Of Mac-1 Results in Novel Diagnostic and Therapeutic Agents Specifically Acting on Activated Monocytes
Authors: Diehl Philipp , Bassler Nicole , Steiner Daniel , Fricke Alba , Peter Karlheinz
Published: April 2024

Introduction:
D
esigned
A
nkyrin
R
epeat
P
roteins (DARPins) are a novel class of highly stable binding proteins (≈10-20kDa) and represent a valuable source for specific binders with picomolar affinities. The I domain is the activation-dependent binding site of the leukocyte integrin Mac-1 that is a central mediator of inflammation. Hypothesis: We assessed whether phage selection against the I domain results in DARPins that specifically bind to activated leukocytes without affecting non-activated ones.

Methods:
Selection was performed on purified mouse I domain using a DARPin phage library with a high diversity (10
10
).

Results:
After 3 panning rounds, specific phages were selected and DARPins expressed with a high yield (≈ 200 mg/L). PMA activation revealed that DARPins bind stronger to activated than to non-activated mouse monocytes (Fig.1). Static and dynamic adhesion assays proved that selected DARPins inhibit binding of Mac-1 to its ligands (Fig.2). Using a peritonitis model, DARPins inhibited leukocyte migration into inflammatory areas, thereby indicating strong therapeutic, anti-inflammatory effects (
control vs DARPin: 940 vs. 230 cells, p<0.02
). DARPins showed strong crossreactivity to activated human Mac-1.

Conclusion:
Selected DARPins specifically bind to activated Mac-1 and can be used for direct monitoring of monocyte activation both in mice and humans. Thereby, based on the novel DARPin format we established a potential anti-monocyte drug that exerts strong anti-inflammatory effects in
in vivo
. Cross-reactivity with human Mac-1 promises translation into a broad spectrum of inflammation driven diseases.
Abstract 9781: A FRET-based Sensor Detects Caveolae as Spatially Distinct Ca2+ Stores in Endothelial Cells
Authors: Isshiki Masashi , Mizuno Risuke , Nishimoto Mitsuhiro , Fujita Toshiro
Published: April 2024

Objective:

Endothelial function is tightly regulated by spatiotemporally organized intracellular Ca
2+
signaling. A variety of Ca
2+
-regulating and Ca
2+
-dependent molecules, such as IP
3
receptor-like protein, Ca
2+
-ATPase and endothelial nitric oxide synthase, are enriched in caveolae, which are mobile and typically shaped as plasmalemmal invaginations or vesicles. As previously reported by us and others, the structure and subcellular distribution of caveolae are critical for Ca
2+
release from endoplasmic reticulum (ER) Ca
2+
stores and for Ca
2+
influx from the extracellular space into the cell. However, the Ca
2+
dynamics inside caveolae have not previously been detected and remain unclear. The aim of this study was to detect and analyze the Ca
2+
changes in subplasmalemmal caveolar vesicles.

Methods:

To target the FRET-based Ca
2+
-sensing protein D1, a mutant of cameleon, to the intracaveolar space, we created a cDNA construct (LOXD1) encoding a chimeric protein with lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) and D1 at its N-terminus and C-terminus, respectively. Localization analysis of LOXD1 and FRET imaging were performed by confocal microscopy. We also analyzed the LOXD1 localization by electron microscopy and the intracaveolar Ca
2+
contents by a pyroantimonate precipitation method.

Results:

First,
immunofluorescence and immunoelectron microscopy confirmed that LOXD1 was mainly expressed outside the plasma membrane, with a significant portion inside the subplasmalemmal caveolae. Second, FRET imaging with LOXD1 detected ATP-induced transient Ca
2+
decreases in the presence or absence of extracellular Ca
2+
. Third, X-ray spectra obtained by spot analyses of electron-opaque pyroantimonate precipitates detected ATP-induced calcium decreases in intracaveolar vesicles.

Conclusions:

Subplasmalemmal caveolae function as mobile, Ca
2+
-releasable Ca
2+
stores in response to IP
3
. This intracellular local Ca
2+
delivery system may contribute to the highly complex spatiotemporal organization of Ca
2+
signaling, and to the versatility of endothelial functions with less Ca
2+
depletion in ER Ca
2+
stores.
Abstract 9819: The Significance of Early Recovery of the ST Segment Depression in the Recovery Period
Authors: Chow Rudy , Chan Sammy , Gin Kenneth , Gao Min , Bennett Matthew T
Published: April 2024

Background Persistence of ST segment depression in recovery signifies a strongly positive ETT, predictive of more ischemia and underlying CAD. It is unclear if early recovery of the ST segment portends a similar prognosis. We sought to determine if persistence of horizontal / down-sloping ST depression into recovery correlates with CAD burden based on myocardial perfusion imaging (MPI). Methods Retrospective analysis of men and women referred for exercise MPI testing was performed. Normal groups were defined as negative ETT (<1mm of ST depression). Those with positive ECG tests were further stratified based on the ST segment at 1 min in recovery. Persistence group was those with >1mm while the Early Recovery group <1mm. Measured MPI variables were summed stress scores (SSS) and high-risk MPI findings. Analysis of variance was used to compare SSS among groups. To assess whether SSS of Early Recovery is no worse than the Normal group, a one-sided 95% confidence limit was calculated for the difference between groups. A non-inferiority margin of -1 was considered clinically acceptable. Results 538 men and 315 women were analyzed. Mean SSS of the Persistence group (7.90 ± 7.69) was significantly different from Early Recovery (4.67 ± 6.18, p<0.001) and Normal (4.78 ± 5.92, p<0.001). Early Recovery was non-inferior to Normals based on SSS (mean difference 0.12, lower 95% CL=-0.66 >-1, p<0.001). Proportion in Early Recovery was similar to Normal but different from Persistence group based on SSS severity (figure). Conclusion Persistence group manifested significantly higher SSS and greater proportion of moderate to high-risk MPI findings when compared to Early Recovery and Normal groups. Furthermore, there was no significant difference in MPI findings between Normal and Early Recovery groups. Early recovery of the ST segment during recovery may represent an underappreciated false positive finding. The results question the accuracy of the ACC/AHA definition of a positive study.
Abstract 9821: Fetal Rhythm Phenotype Predicts LQTS Mutation: Risk Stratification of Perinatal Long QT Syndrome
Authors: Cuneo Bettina F , Barczak Jeannette , Sallee Denver , Benson D. Woodrow
Published: April 2024

Introduction:
Torsade de pointe (TdP) and/or 2° atrioventricular block (2° AVB) are signature rhythms for perinatal LQTS known for their high morbidity and mortality. We hypothesized that the clinical profile of patients with complex fetal arrhythmias might be mutation specific.

Methods:
Perinatal records of subjects with LQTS exhibiting complex fetal arrhythmia were reviewed. Fetal echocardiograms, neonatal ECG and genetic testing were evaluated.

Results:
We studied 11 LQTS subjects exhibiting complex fetal arrhythmias. Mutation in a known LQTS gene was identified in 9: SCN5A (5), KCNH2 (2) and KCNQ1 (2). Most mutations were de novo including 4 SCN5A-1623Q. TdP occurred in 8 cases (7 prenatal, mean gestational age=30.5 weeks). Most fetuses with TdP also had 2° AVB, but 3 cases had 2° AVB alone. TdP exhibited 2 patterns: fast (>270 bpm) and incessant or slow (<250 bpm) and intermittent. All cases with SCN5A mutation had fast-incessant TdP, while cases with KCNH2 mutations had slow-intermittent TdP. Cases with KCNQ1 mutations had 2° AVB. Fetuses with TdP were delivered earlier (33.6 weeks) than those with 2° AVB (38.5 weeks). Neonatal QTc intervals were 652 ± 42 (in utero TdP) and 507 ± 43, p=0.01 (in utero 2° AVB). Prenatal treatment was administered in 6 cases without maternal complications; 4 fetuses improved and TdP ceased in 2. Despite medical and pacemaker therapy, cardiac arrest (n=6) resulting in sudden death (n=2) were common.

Conclusion:
Complex rhythm phenotypes of fetal LQTS have mutation specific features that may allow risk stratification in these high risk patients.
Abstract 9829: Subclinical Atherosclerosis in Asymptomatic Subjects Referred for Risk Stratification: A Comparison of Carotid Ultrasound, Coronary Artery Calcium Scoring and Coronary Computed Tomography Angiography
Authors: Schroeder Benjamin D , Mancini G. B. John , Leipsic Jonathon , Heilbron Brett , Francis Gordon A , Taylor Carolyn M
Published: April 2024

Introduction:
In subjects free of known vascular disease, current guidelines recommend lipid targets according to global risk of cardiovascular events. In select populations, imaging is recommended for refining clinical risk. The purpose of this study was to compare three imaging modalities coronary artery calcium scoring (CACS), carotid ultrasound (US) and coronary computed tomography angiography (CCTA) in a population referred for risk stratification.

Hypothesis:
We hypothesized that diverse definitions of early atherosclerosis utilized by differing modalities would affect perceived prevalence of subclinical atherosclerosis and consequently, assessment of risk. We sought to determine the degree of concordance among these definitions.

Methods:
Subjects free of known vascular disease scheduled to undergo a carotid US for clinical risk stratification were invited to undergo CCTA/CACS. Subjects on lipid lowering therapy > 3 months were excluded. All images were assessed by an experienced core laboratory. Carotid intima media thickness ≥75
th
percentile for age and sex, CACS > 0 and detection of either carotid or coronary artery plaque were indicators of atherosclerosis.

Results:
Fifty patients were included. Median age was 53 years; 54% were men. Atherosclerosis was seen in 28%, 78% and 90% of subjects using CACS, CCTA and carotid US, respectively, with all subjects demonstrating one or more markers or findings on at least one method. In the 36 patients with CACS = 0, 69% and 86% had atherosclerosis on CCTA and carotid US, respectively. Maximal concordance (68%, p = 0.021) between carotid US and CCTA was seen when carotid US showed the presence/absence of any plaque with a maximal thickness of ≥ 1.5 mm.

Conclusions:
In this detailed analysis, all subjects identified to warrant further risk stratification had findings indicating subclinical atherosclerosis on at least one modality. Concordance between the modalities was highly variable, dependent upon the specific definition used. Carotid US and CCTA detection of plaque were more sensitive than CACS > 0. Given strong evidence for low CV risk in patients with CACS = 0, the threshold of subclinical disease at which to treat using Carotid US or CCTA plaque warrants further consideration and caution.
Abstract 9922: The Induction of YAP Expression Following Arterial Injury is Crucial for Smooth Muscle Phenotypic Modulation and Neointima Formation
Authors: Wang Xiaobo , Hu Guoqing , Wang Yong , Zhou Jiliang
Published: April 2024

Rationale:
Abnormal proliferation and migration of vascular smooth muscle cells (SMCs) are the key events in the progression of neointimal formation in response to vascular injury. Previous studies have shown that YAP is a potent oncogene promoting cell migration and proliferation, while the role of YAP in vascular diseases remain unknown.

Objective:
The goal of this study is to investigate the functional role of YAP in smooth muscle phenotypic modulation in vitro and in vivo.

Methods and Results:
In vitro in cell culture and in vivo in both mouse and rat arterial injury models YAP expression is significantly induced and correlated with the vascular SMC synthetic phenotype. YAP is also highly expressed in human carotid atherosclerotic plaque and localized in the majority of SMCs. Over-expression of YAP promotes SMC migration and proliferation while attenuating smooth muscle contractile gene expression. Conversely, knocking-down endogenous YAP in SMCs up-regulates smooth muscle gene expression but attenuates SMC proliferation and migration. Consistent with this, knocking-down YAP expression in a rat carotid balloon injury model attenuates injury-induced smooth muscle dedifferentiation and neointima formation. Furthermore, carotid artery ligation in mice with genetic deletion of YAP specifically in SMCs leads to increase smooth muscle-specific gene expression and reduction of neointima formation.

Conclusion:
YAP plays a novel integrative role in smooth muscle phenotypic modulation by inhibiting smooth muscle-specific gene expression while promoting smooth muscle proliferation and migration in vitro and in vivo. Blocking the induction of YAP would be a potential therapeutic approach for ameliorating vascular occlusive diseases.
Abstract 9925: Association between Resting Heart Rate, Chronotropic Index and Long-term Outcomes in Patients with Heart Failure Receiving Beta-blocker Therapy. Data from the HF-ACTION Trial
Authors: Dobre Daniela , Zannad Faiez , Keteyian Steven J , Stevens Susanna R , Rossignol Patrick , Kitzman Delane K , Landzberg Joel , Howlett Jonathan , Kraus William E , Ellis Stephen J
Published: April 2024

Aim
s: To assess the association between resting heart rate (HR), chronotropic index (CI) and clinical outcomes in patients with chronic heart failure (HF) on optimized β-blocker therapy.

Methods:
We performed a sub-study in 1118 patients with chronic HF and reduced ejection fraction (EF <35%) who were enrolled in the HF-ACTION trial. We included patients in sinus rhythm who received a β-blocker and who performed an adequate symptom-limited maximum exercise test. Chronotropic Index was calculated as a percentage of predicted maximum HR reserve achieved, by using the equation (220-age) for estimating maximum HR. A sensitivity analysis using an equation estimating maximum HR for patients with HF taking β-blockers [(119 + (resting HR/2) - (age/2) - (5 * bike)] was also performed. Cox proportional hazards models were fit to assess the association between CI and clinical outcomes.

Results:
Median (25
th
, 75
th
percentiles) follow-up was 32 (21, 44) months. In a multivariable model including resting HR and CI as continuous variables, neither was associated with the primary outcome of all-cause mortality or hospitalization. However, in multivariable analysis, each 0.1 unit decrease in CI below 0.6 was associated with 17% increased risk of all-cause mortality (Hazard Ratio 1.17, 95% Confidence Interval 1.01-1.36; p=0.036) (figure), and 13% increased risk of cardiovascular mortality or HF hospitalization (Hazard ratio 1.13, 95% Confidence Interval 1.02-1.26; p=0.025). CI did not retain statistical significance when dichotomized at a value ≤0.62 as opposed to analysis of CI as a continuous variable. Sensitivity analysis showed a similar relationship between CI and outcomes.

Conclusion:
In patients with chronic HF receiving optimal medical therapy, a decrease in CI below 0.6 was associated with the risk of adverse clinical outcomes. These data support a strategy of including improved heart rate response to exercise, as a therapeutic target in the chronic HF population.
Abstract 9943: Aged Garlic Extract Plus Coenzyme Q10 Significantly Reduce Perceived Mental Stress, Inflammaion and Subclinical Atherosclerosis in Firefighters ‰the FAITH Randomized Clinical Trial
Authors: Nabavi Larijani Vahid , Hajsadeghi Fereshteh , flores Ferdinand , budoff Matthew , Ahmadi Naser
Published: April 2024

Background:
We previously reported that Aged Garlic Extract (AGE) is associated with significant reduction of subclinical atherosclerosis measured by coronary artery calcium (CAC) in asymptomatic individuals. Stressful lifestyle is a well-known risk factor of atherosclerosis. In the current study, we evaluate the effect of AGE plus CoQ10 on perceived mental stress score (PMSS), inflammation and CAC in Firefighters with highly stressful lifestyle.

Methods:
In this placebo-controlled, double blinded, randomized trial, 65 firefighters, age 55±6 years, 100% male, with intermediate risk for coronary artery disease (CAD) subjects were randomized to AGE and CoQ10 vs. placebo for 1-year. Subjects’ mental stress was assessed as perceived mental stress score (PMSS) using validated perceived mental stress questionnaire (PSQ). PMSS, high sensitive C reactive protein (CRP) and CAC were measured at baseline and follow up.

Results:
There was no significant difference between PMSS, CRP, CAC and other risk factors at baseline (p>0.5). At-year follow-up, PMSS reduction was significantly higher in AGE plus CoQ10 as compared to placebo (-10.6% vs. 14.7%, p=0.001). After adjustment for risk factors, AGE plus CoQ10 was independently associated with significant reduction in PMSS, CRP and CAC (p<0.05) (Table). In which, the likelihood of decrease in PMSS was 84% higher with AGE plus CoQ10. Decrease in PMSS in response to AGE plus CoQ10 was significantly associated with decrease in CRP and CAC (p<0.05).

Conclusion:
This study reported the beneficial effect of AGE-CoQ10 on mental stress in subjects with highly stressful lifestyle independent of risk factors. Furthermore, it highlights the association between decrease in mental stress , inflammation and atherosclerosis in response to such therapy.
Abstract 9954: 5-Lipoxygenase Inhibitor VIA-2291 (Atreleuton) Intake Improves Left Ventricular Ejection Fraction in Patients with Recent Acute Coronary Syndrome
Authors: Ram Reuben J , Nabavi Larijani Vahid , Prabhu Sachidanand , Dialing Christopher , Ardestani Armand , Ram Nina , Ahmadi Naser , Ibrahim Reda , Pressacco Josephine , Tardif Jean-Claude , Budoff Matthew J
Published: April 2024

Background:
Previous studies have shown coronary artery syndrome can result in left ventricular myocardial remodeling (LVMR); and progressive LVMR after infarction could lead to decline in ejection fraction. In this study we evaluated the effect of a potent and selective 5-Lipoxygenase inhibitor, VIA-2291, on Left Ventricular Ejection Fraction (LVEF) in patients with recent Acute Coronary Syndrome (ACS) on top of standard medical therapy.

Methods:
This is a double blinded: placebo controlled: dose ranging: randomized: multicenter trial (clinicaltrials.gov
NCT00358826
) of 56 individuals with recent ACS who were recruited and followed for 24 weeks in an imaging substudy. Subjects were randomized to four study arms including: 25 mg, 50 mg, and 100 mg of VIA-2291 as well as placebo. LVEF and Stroke Volume (SV) were measured post-hoc by contrast enhanced Cardiac Computed Tomographic Angiography on GE Advantage Windows 4.4 Workstations (GE Healthcare, Milwaukee, WI).

Result:
There were no major differences between traditional cardiovascular risk factors among the 4 randomized study arms. LVEF improved dramatically in subjects who had taken VIA-2291 vs. placebo: 1.8±8.4 vs. -3.0±9.3 (p=0.0001). Similarly SV improved significantly with VIA-2291 vs. placebo: 3.9±15.9 vs. -4.8±17.2 (p=0.0001). VIA-2291 demonstrated a dose dependent effect on LVEF and SV with largest benefit achieved with the highest dose of the drug (100mg) vs. Placebo; LVEF and SV: 2.64±6.06 and 4.65±14.01, p=0.0001, respectively (Figure 1). Of note, the placebo group was shown to have a decrease in LVEF and SV -3.1±9.3 and -4.8±17.2, respectively, which can be attributed to post-ACS myocardial-remodeling.

Conclusion:
The addition of VIA-2291 to standard of care medical regimen is able to improve ejection fraction dramatically in patient with recent coronary artery syndrome over a 6 month follow-up period. Benefits of VIA-2291 are dose dependent.
Abstract 9974: A Novel Comprehensive RV Strain Analysis: Echocardiographic Approach to Define a Normal Adult Population
Authors: Forsha Daniel E , Risum Niels , Smith Phillip B , Kropf Andrea , Rajagopal Sudarshan , Samad Zainab , Kanter Ronald J , Piers Barker , Kisslo Joseph
Published: April 2024

Introduction:
This study was performed to test the feasibility of and to establish normal ranges of a novel 3 view RV strain analysis. Such an approach is a necessary precursor for more detailed studies of RV regional dysfunction since RV failure is the primary problem in many congenital heart disorders. To date, 2D speckle-tracking strain experience with the RV is limited.

Hypothesis:
This novel methodology is feasible and will allow significantly improved RV data to be produced via strain analysis.

Methods:
Twenty-five healthy subjects were prospectively studied from the apical position using a 3 view RV approach with views equivalent to a LV 60º rotational model (Figure). Subjects received a complete echo optimized for 18 segment (SEG) RV strain analysis using a GE Vivid e9 with off-line 2D speckle-tracking analysis performed using EchoPAC BT11 software.

Results:
Mean age was 30 years (range 20-52, 36% male). All had a normal QRS duration, TAPSE, and LVEF. Adequate tracking was obtained in 457/468 of all segments (98%). Using global functional RV analysis, the global peak longitudinal systolic strain (PLSS) mean was -23.5% (range -18.1% to -27.3%). Regional PLSS was greatest in the free-wall > apical > septal segments (p<0.001). The standard deviation of time to peak intervals (SDTTP) in the 18-SEG model was 26.7±8.2 ms (range 14.9 - 41.9ms) versus 22.5±9.2 ms in the traditional apical 4 chamber single view (p=0.004). No dyssynchronous patterns were observed. Coefficients of variation for independent intra/inter-observer measures were 6% and 9% for global PLSS and 12% and 11% for SDTTP.

Conclusions:
The 18-SEG regional RV strain analysis is feasible, and normal ranges follow a consistent synchronous pattern. This novel comprehensive methodology adds information to the traditional model and provides a baseline for further study of regional RV strain in patients with suspected RV dysfunction and/or abnormal contraction patterns.
Abstract 9976: Human Atrial Fibrillation Initiates by Formation of a Dominant Spiral Wave at the Site Where Triggers Cause Dynamic Conduction Slowing
Authors: Schricker Amir , Lalani Gautam , Krummen David E , Narayan Sanjiv M
Published: April 2024

Introduction
Triggers may initiate human atrial fibrillation (AF), but by unclear mechanisms. We hypothesized that triggers would dynamically slow atrial conduction velocity, to enable the formation of a single localized spiral wave or repetitive focal beat that may drive the atria into AF.

Methods
We studied 13 patients at clinically-indicated AF ablation (5 persistent, age 63±11 years, LA size 43±6mm) in whom we placed 64-pole basket catheters (Boston Scientific, Natick, MA) in both atria. AF was initiated by accelerating pacing initially from 120 beats/min to AF onset. We constructed isochronal maps of both atria for beats leading to and including the first cycles of AF. We computed conduction time to each bi-atrial electrode at each rate, thus defining rate-dependence (restitution) of conduction throughout the atria.

Results
AF initiated in the left atrium in 13/13 patients. Notably, atrial conduction slowed dynamically with rate at the site of AF onset in 8 patients, either gradually (Figure A) or abruptly. In all patients, spatial mapping showed that triggers initiated AF at a site of dynamic conduction slowing (76%±60%) by the formation of a single spiral wave (n=7; figure B) or repetitive focal beat (n=1). Notably, these regions were not the slowest to activate at baseline. Figure A shows dynamic conduction velocity slowing only at faster rates (Fig A, steep curve) at a site in the septal posterior LA, which enabled block (Figure B, site marked *) and formation of a spiral wave (Fig B, curved arrow) that initiates AF.

Conclusions
Triggers initiate human AF by causing dynamic conduction slowing, enabling the formation of a single reentrant spiral wave (or repetitive focal beat) that drives the atria into AF. Of note, these sites did not exhibit conduction slowing at baseline, showing the central dynamic role of the trigger in AF initiation. Future studies should modulate conduction slowing from a trigger to prevent AF initiation.
Abstract 9998: Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Cathepsin K-Deficient Mic
Authors: Jiang Haiying , Cheng Xian Wu , Shi Guo-Ping , Hu Lina , Song Haizhen , Inoue Aiko , Koike Teruhiko , Kuzuya Masafumi
Published: April 2024

Background

: Cysteine protease cathepsins (Cats) have been implicated in the process of neovascularization. However, the exact roles of individual Cat proteins in vessel formation are poorly understood.

Methods and Results

: To study the putative role of cathepsin K (CatK) in ischemia-induced neovascularization, a hindlimb ischemia model was applied to CatK+/+ and CatK-/- mice. Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in CatK-/- young and old mice remained impaired throughout the follow-up period. At day 28, anti-L-lectin immunohistochemical staining revealed less developed capillary formation in both old and young CatK-/- mice compared with age-matched CatK+/+ mice. CatK deficiency reduced macrophage infiltration in the ischemic muscle. An aortic-ring culture assay showed a markedly impaired angiogenic response in CatK-/- mice. Aorta-derived endothelial cells and bone marrow-derived endothelial progenitor cell (EPC)-like c-Kit+ cells from CatK-/- showed marked impairment of invasive and proliferative abilities. On day 7, plasma and ischemic tissues of CatK+/+ showed reduce vascular endothelial growth factor protein and stromal cell derived factor-1. Flow cytometry showed that the numbers of EPC-like CD31+/c-Kit+ cells in peripheral blood markedly decreased in CatK-/- mice. Transplantation of bone marrow-derived mononuclear cells from CatK+/+ mice restored neovascularization in CatK-/- young mice.

Conclusions

: These data suggest that CatK deficiency impairs ischemia induced neovascularization through a reduction of endothelial cell and EPC functions and EPC mobilization.
Abstract 17986: Multiple Single Day Blood Pressure Measurements and Their Impact on Coronary Heart Disease, Stroke, and Heart Failure Risk Prediction: The Atherosclerosis Risk In Communities (ARIC) Study
Authors: Ogunwale Abayomi , Morrison Alanna C , Dodge Rhiannon , Virani Salim , Taylor Addison , Gottesman Rebecca , Yang Eric , Wei Peng , Boerwinkle Eric , Heiss Gerardo , Ballantyne Christie , Nambi Vijay
Published: April 2024

BACKGROUND:
Although systolic blood pressure (SBP) varies through the day, single SBP measures are used in all coronary heart disease (CHD), heart failure (HF) and stroke risk prediction equations. Changes in SBP clearly affect estimated risk. However, the magnitude of change in risk when different SBP measures performed within one day are used in risk equations is not known.

METHODS:
Same day multiple SBP measurements (sitting, standing and supine) were performed by certified technicians using a Dinamap device in 11,075 ARIC study participants (mean age 53.9 ± 5.7 years, 57% with history of smoking, 10% diabetic and 31% hypertensive). We estimated 10 year CHD, HF and stroke risks for each SBP measure and classified individuals as 0-5%, 5-10%, 10-20% and >20% risk.Then, we evaluated changes in individual risks within a day.

Results:
(Table): Substituting mean sitting SBP for standing and supine SBP in the Framingham CHD Risk Score (FRS) reclassified 8.3% and 10.2% of the subjects, and in the ARIC Coronary Risk Score (ACRS), 7.1% and 9.6%, respectively. Similarly, when stroke and HF risks were evaluated using ARIC risk scores 11.7% and 12.3% were reclassified when standing SBP was used, and 10.7% and 11.7% were reclassified with supine SBP measures. The maximum changes in an individual’s estimated 10 year risk were 21%, 26% and 24% for CHD, stroke and HF risk, suggesting greater than one risk category (e.g.,low to high risk) change in a day. When different sitting SBP measures (taken within minutes of each other) were used, 6.7%, 6.5%, 6.5% and 8.0% of subjects were reclassified when FRS, ACRS, ARIC stroke and HF risks were estimated.

CONCLUSION:
SBP changes within a day can result in statistically significant changes in estimated CHD, stroke, and HF risk. Our study has implications for the use of a single SBP measure to determine an individual’s cardiovascular risk, and raises questions on the utility of current risk prediction algorithms in patient management.
Abstract 18061: Attenuated Aortic Dilatation, Not Increased Wall Stiffness Best Explains the Rise in Pulse Pressure in Women With Aging: Results From the Baltimore Longitudinal Study of Aging
Authors: AlGhatrif Majd , Strait James B , Morrell Chris , Canepa Marco , Wright Jeanette , Elango Palchamy , Scuteri Angelo , Najjar Samer S , Ferrucci Luigi , Lakatta Edward G
Published: April 2024

BACKGROUND:
While women have a greater increase in pulse pressure (PP) with aging, aortic pulse wave velocity (PWV), a direct measure of arterial stiffness, is not higher in women than men. We hypothesized that a slower increase in aortic root diameter (AoD), rather than greater arterial wall stiffening per se, best explains the rise of PP in women with aging compared to men.

METHODS AND RESUTLS:
A total of 257 men and 310 women from the Baltimore Longitudinal Study of Aging, aged 25 to 93 years, had 2-8 repeated measures of PP, PWV, and AoD by echocardiography between 1988 and 2013. Linear Mixed-effects (LME) models were used to examine the longitudinal changes in PP, PWV, and AoD indexed to BSA. Age was expressed as First-age (age at entry), and Time (follow up time), to differentiate cross-sectional differences from longitudinal changes over time. Model-predicted values were plotted to illustrate concurrent trajectories of PP, PWV, and AoD (Fig. 1). Men had a pronounced acceleration in PWV increase, but a deceleration in PP increase with age beyond the 5
th
decade [β= 0.21,
P=
0.0004, and β= - 0.12,
P=
0.0419, for (Time х First-age
2
) in PWV and PP, respectively]; note the changes of the solid line’s slope in Fig.1A, B. On the other hand, women had an acceleration in PWV increase with age [β= 0.19,
P=
0.0318, for Time х First-age] concordant with a steady increase in PP [β= 4.7,
P<
.0001, for Time]. These trajectories resulted in a higher PWV, but a lower PP in men than women beyond the 5
th
decade (Fig 1A, B). The dissociation between PP and PWV longitudinal changes in men was accompanied by a steeper increase in AoD in men than women resulting in greater AoD in men beyond the 5
th
decade (β=0.04,
P=
0.0146) (Fig1C).

CONCLUSION:
The greater acceleration in AoD in men likely offsets the effect of elevated arterial stiffness blunting the increases in pulse pressure; lesser AoD dilatation in women potentially leaves arterial wall stiffness unopposed, giving rise to a greater increase in PP in women with aging.
Abstract 18077: Endothelial Behavior and Signaling on Micro and Submicro- Patterned Titanium
Authors: Vandrangi Prashanthi , Gott Shannon , Kozaka Ryan , Rao Masaru P , Rodgers Victor G
Published: April 2024

Reestablishment of functional endothelium is crucial to long-term success in vascular stenting. However, numerous studies have shown potential for endothelial dysfunction on current drug eluting stents (DES), due to their reliance upon anti-inflammatory and immunosuppressive drugs for suppression of neointimal hyperplasia. We report results demonstrating that EC adhesion, proliferation, and morphology on Ti substrates can be enhanced significantly in vitro through surface patterning with gratings composed of periodic arrays of grooves with widths as small as 0.5 μm. We further asses the EC function on these surfaces. Patterned substrates were fabricated using our Ti deep reactive ion etching (Ti DRIE) process. After substrate sterilization, HECs were seeded and cultured for 1-3 days. Substrates were then rinsed with phosphate buffered solution (PBS) and adherent HECs were fixed and permeabilized and immuno-histo chemistry was performed and imaged using confocal fluorescent techniques, and processed. Figure 1 shows HECs aligned in the direction of sub-micron grooves and the corresponding signaling results. Activation of vWF, a vital anti-thrombotic, was significantly enhanced on all grating sub-patterns relative to unpatterned control (p value=0.05). Activation of eNOS, a potent vasodilator, generally increased with decreasing feature size. The phosphorylation of AMPK, which is reported to enhance cell polarity and division, was significantly higher on submicron-patterns of 0.75 and 0.5 μm (p value=0.5). Expression of VE Selectin, a metastatic cancer marker, was suppressed on most gratings. Finally, VCAM1, an anti-inflammatory, was negatively transcribed on sub-μm gratings (p value=0.05). These results demonstrate that nanopatterning can promote activation and suppression of atheroprotective and atheroscleotic biomolecules in vitro, thus suggesting promise for promoting native functionality in vivo.