bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9611: Enhancing the “Paracrine Effects” of Mesenchymal Stem Cells to Recover Damaged Myocardium by the Use of Cell-Sheets
Authors: Narita Takuya , Shintani Yasunori , Ikebe Chiho , Harada Narumi , Kaneko Masahiro , Campbell Niall G , Sawhney Vinit , Coppen Steven R , Yashiro Kenta , Suzuki Ken
Published: April 2024

Recent research has shown that transplantation of mesenchymal stem cells (MSCs) recovers failing hearts mainly
via
paracrine effects and has prompted clinical trials of intramyocardial injection of MSC suspensions. However, this method is associated with trypsinisation-induced MSC damage and injection-related injury/inflammation of host myocardium. It is now possible to generate “cell-sheets” by means of temperature-responsive culture dishes without using disruptive reagents. Epicardial placement of MSC-sheets will be able to deliver MSCs with higher viability and functionality whilst obviating damage to the host myocardium. This will enhance the paracrine effects, by improving both MSC secretion and host myocardium response, leading to amplified therapeutic effects.

Methods & Results:
After coronary artery ligation in female rats, 4 million bone marrow derived MSCs from syngeneic male rats were grafted by either intramyocardial injection (IM) or cell-sheet placement (CS). Sham treated rats served as control (Cont). Donor MSC survival was markedly increased in CS compared to IM. The majority of MSCs in CS remained at the epicardial surface, avoiding myocardial accumulation of inflammatory cells. Shortly after sheet placement, the epicardium degenerated, allowing permeation of MSC-secreted mediators into the myocardium. Differentiation of donor MSCs to cardiac or mesenchymal lineages was not observed. IM showed upregulation of HIF1α, bFGF, IL10, VCAM1, MMP2, TIMP1, IGF1, SDF1, which was associated with favorable modulations in host cardiac tissues. Of note, these molecular and cellular changes were significantly amplified in CS, in correlation to further enhanced cardiac function.

Conclusion:
The cell-sheet technique improved donor MSC engraftment whilst preserving the host myocardium, resulting in augmentation of MSC-derived paracrine effects, compared to the current method. These data encourage clinical application of this approach.
Abstract 9612: Does quantification of Epicardial Adipose Tissue (EATv) and Intrathoracic Fat (ITFv) Volume with Noncontrast Cardiac Computed Tomography (CCT) improve Coronary Events (CE) Prediction Over Clinical Information and Coronary Artery Calcium Score (CACS)?
Authors: Forouzandeh Farshad , Chang Su Min , Muhyieddeen Kamil , Zaid Rasheed R , Trevino Alejandro R , Xu Jiaqiong , Nabi Faisal , Mahmarian John J
Published: April 2024

Background:
CCT allows for calculation of CACS and measurement of EATv and ITFv. It is unclear whether EATv and ITFv provide additional value over CACS and clinical information in predicting CE.

Methods:
760 consecutive symptomatic patients without known coronary disease underwent CCT and were followed up to 5 years (median 3.3 years) for CE (cardiac death, non fatal MI, and acute coronary syndrome with >70% coronary artery stenosis). The mean age was 54.4 ±13.7 years, 60 % were female, 15% were diabetics, mean body mass index (BMI) of 30.6 kg/m
2
and mean Framingham risk score (FRS) of 8.2. The ITFv and EATv were calculated with semiautomated method. Fat tissue were automatically recognized by threshold between -40 and-200 HU.

Results:
Compared to 715 event-free patients, the 45 patients who had CE were older (64.8 vs 53.7 y/o p<0.001), more male (60% vs 40% p=0.008), higher mean FRS (14.3 vs 7.8 p<0.001) and higher median CACS (268 vs 0 p <0.001). They also had higher median EATv (154 vs.116 ml, p = 0.006) and ITFv (330 vs 223 ml, p = 0.001), higher prevalence of EATv >125 ml (67% vs. 44%, p = 0.005)and ITFv>250 ml (64% vs. 42%, p = 0.003). Both EATv and ITFv were predictors of CE and remained so after adjustment for FRS, BMI and CACS >400 (Table 1). The area under the curve from ROC analyses showed trends to improve CE prediction when fat volume was added to FRS, BMI and log (CACS±1) (0.839 for EATv>125ml, 0.843 for ITFv>250ml vs. 0.828, p=0.14 and 0.11 respectively). On the other hand, CACS significantly improved the prediction when added to FRS and BMI (0.828 vs 0.724 p=0.001)

Conclusions:
Symptomatic patients with CE had larger ITFv and EATv and higher CACS. Although both EATv and ITFv provided some incremental value over clinical information, CACS remained the strongest predictor of outcome
Abstract 9635: A Novel in vitro Model of Danon Disease Confirms the Critical Role of LAMP2 in Regulating Autophagy
Authors: Clegg Stacey , Gong Qiuming , Zhou Zhengfeng , Adler Eric
Published: April 2024

Introduction:
Danon disease is an X-linked cardiomyopathy caused by mutations in the lysosomal associated membrane protein 2 (LAMP2). LAMP2 plays a critical role in autophagy, but the mechanisms in which mutations lead to myocyte dysfunction are poorly understood. We identified a novel frame shift mutation that introduces a premature termination codon (PTC) in the LAMP2 gene in a patient with Danon disease. Degradation of PTC-containing mRNA transcripts by nonsense mediated decay (NMD) has been shown in a variety of heart diseases. We hypothesized that 1) the mechanism of LAMP2 dysfunction in this patient is NMD mediated, and 2) induced Pluripotent Stem (iPS) cell-derived myocytes generated from these fibroblasts would show evidence of impaired autophagy.

Methods:
Dermal fibroblast lines were established from a patient with Danon disease and used for RNA and protein assays. Fibroblasts were subsequently used to create iPS cell-derived cardiomyocytes using previously described techniques. Immunohistochemistry and protein gel electrophoresis of the autophagosome associated protein, LC3-II, were used to assay for autophagic function. Ultrastructural studies were performed using electron microscopy.

Results:
Patient fibroblasts were shown to completely lack the LAMP2 protein. Treatment with the protein synthesis inhibitor cyclohexamide stabilized LAMP2 mRNA levels, suggesting this LAMP2 mutation is targeted by NMD. Compared to wild type cells, Danon disease iPS-derived cells demonstrated reduced basal levels of the autophagosome-associated protein LC3-II, suggestive of impaired autophagy. Electron microscopy of iPS cells showed excessive intracytoplasmic vacuoles consistent with the disease phenotype.

Conclusions:
We have successfully created the first in vitro human model of Danon disease. Using this system, we identified NMD as a novel mechanism responsible for LAMP2 dysfunction in a patient with Danon disease. Furthermore, we confirmed the critical role of LAMP2 in the regulation of autophagy. This study highlights the utility of this in vitro system for elucidating the pathophysiology of inherited cardiovascular disease.
Abstract 9649: Lipid-modifying Effects of Anacetrapib in Patients with Lower versus Higher Baseline Levels Of HDL-C, LDL-C, And TG: Pre-Specified Subgroup Analyses of the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) Trial
Authors: Brinton Eliot , Liu Sherry , Stepanavage Michael , Cannon Christopher P , Davidson Michael , Gotto Antonio M , Shah Sukrut , Dansky Hayes , Mitchel Yale , Barter Philip
Published: April 2024

Purpose
: Low HDL-C is a risk factor for coronary heart disease which partly accounts for residual risk despite statin therapy. After 24 weeks of treatment, the addition of anacetrapib (ANA), a cholesteryl ester transfer protein (CETP) inhibitor to statin therapy increased HDL-C by 138% and reduced LDL-C by 40% in a 1623 patient safety and lipid efficacy Phase III trial (DEFINE). Sub-group analyses were performed to determine the degree to which ANA raises HDL-C and lowers LDL-C in patients with low baseline HDL-C and in patients with diabetes and other subgroups.

Methods:
Percent placebo-corrected HDL-C increases and LDL-C decreases from baseline after 24 weeks of ANA, 100 mg/day, were compared among patients according to baseline HDL-C, LDL-C, and TG levels above or below the median and in patients with diabetes.

Results:
Median baseline HDL-C, LDL-C, and TG were 40 mg/dL, 81 mg/dL, and 128 mg/dL, respectively. ANA produced robust increases in HDL-C in patients with baseline HDL-C below (152%) and above (127%) the median. In the lowest baseline quartile of HDL-C (15 to 34 mg/dL) levels also increased to a mean on-treatment HDL-C of 85 mg/dL. The percent increase in HDL-C was similar in patients with lower vs. higher baseline TG levels. ANA increased HDL-C similarly in diabetics compared to non-diabetics (130% vs 150%) with a mean on-treatment HDL-C of 100 vs. 102 respectively. The percent reduction in LDL-C with ANA was generally similar in patients with lower vs higher baseline LDL-C, HDL-C or TG levels and in patients with or without diabetes.

Conclusion:
ANA robustly increased HDL-C in all patients especially those with low HDL-C. Reductions in LDL-C with ANA were independent of baseline LDL-C, HDL-C, or TG levels. The clinical impact of these lipid-modifying effects of ANA in these sub-groups will be assessed in REVEAL-HPS3/TIMI55, a 30,000 patient clinical outcomes trial.
Abstract 9659: Combination Therapy with Olmesartan and Azelnidipine Exerts Anti-Atherogenic Effects in Diabetic Apolipoprotein E-Deficient Mice
Authors: Noda Kazuki , Hosoya Maki , Nakajima Sota , Ohashi Junko , Shimokawa Hiroaki
Published: April 2024

Background:
We have recently demonstrated that combination therapy with olmesartan (OLM), an angiotensin type 1 receptor blocker, and azelnidipine (AZL), an L-type Ca channel blocker, improves endothelial function more than each monotherapy in diabetic Apolipoprotein-deficient (ApoE
-/-
) mice. In this study, we further examined whether this also is the case for atherosclrosis.

Method and Results:
We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE
-/-
mice. The diabetic ApoE
-/-
mice were administered oral vehicle (untreated), OLM (30 mg/kg/day, PO), AZL (10 mg/kg/day, PO), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) for 5 weeks (n=8 each). Blood pressure was significantly elevated in the untreated group but was normalized by OLM+AZL or HYD. At 5 weeks, the extent of oil-red O staining in the aorta was markedly increased in the untreated group and was significantly ameliorated in the OLM+AZL group (P<0.05). In the HYD group, despite the normalization of blood pressure, the extent of atherosclrosis in the aorta was comparable with that in the untreated group. Similarly, both perivascular fibrosis and medial thickness of the epicardial coronary arteries were increased in the untreated group, both of which were ameliorated only in the OLM+AZL group (both P<0.05). In addition, cross-sectional area of cardiomyocyte was significantly increased in the untreated group and was significantly ameliorated only in the OLM+AZL group (P<0.05). To examine the mechanisms involved, dihydroethidium staining was performed, which showed that aortic ROS production was significantly increased in the untreated group and was significantly inhibited only in the OLM+AZL group (both P<0.05). Furthermore, both eNOS expression and activity (as examined by its phosphorylation at serine 1177) were increased only in the OLM+AZL group (P<0.05). The expression of RAGE (receptor for advanced glycation end-products) also tended to decrease in the AZL and OLM+AZL groups compared with the untreated group (both P=0.05).

Conclusion:
These results indicate that the combination therapy with OLM and AZL exerts anti-atherogenic effects more than each monotherapy in ApoE
-/-
mice in vivo, for which reduction of oxidative stress may be involved.
Abstract 9683: Acetylcholine-Provoked Diffuse Coronary Spasm is Frequently Observed in Female Patients with Coronary Vasospastic Angina Without Severe Coronary Organic Stenosis
Authors: Sato Koji , Kaikita Koichi , Nakayama Naoki , Horio Eiji , Ono Takamichi , Ohba Keisuke , Tsujita Kenichi , Hokimoto Seiji , Sumida Hitoshi , Sugiyama Seigo , Yamabe Hiroshige , Ogawa Hisao
Published: April 2024

Coronary Vasospastic angina (VSA) plays an important role in the pathogenesis of ischemic heart disease. However, the relation between angiographic variation of acetylcholine (ACh)-induced coronary spasm and clinical features in VSA patients is not well understood. We analyzed retrospectively angiographic appearance of coronary vasomotor response induced by ACh injection into left coronary artery (LACh) in 1760 consecutive patients who had rest angina-like chest pain between January 1991 and December 2010. Coronary spasm induced by LACh test was defined as a total or subtotal obstruction (focal spasm), or severe diffuse constriction (diffuse spasm) of left epicardial coronary artery associated with transient myocardial ischemia as evidenced by ischemic ST-segment changes on ECG. Of total 1760 patients, 754 (43%) patients were positive for LACh test on the basis of positive criteria (329 diffuse and 425 focal spasm). Patient characteristics were compared between LACh-positive and -negative groups. Rate of smoking, dyslipidemia, family history of ischemic heart disease (IHD), comorbidity of coronary organic stenosis, and myocardial lactate production were significantly higher in LACh-positive than negative groups (49.7% vs. 42.7%, p=0.005, 48.0% vs. 38.1%, p<0.001, 16.2% vs. 9.6%, p<0.001, 26.9% vs. 14.1%, p<0.001, and 60.9% vs. 13.9%, p<0.001, respectively). Next, we analyzed relation between angiographic variation of LACh-provoked coronary spasm and clinical features in VSA patients. Multiple logistic regression analysis revealed that female gender and low comorbidity rate of coronary organic stenosis were significantly associated with diffuse spasm subtype (OR 2.97; 95%CI: 1.90 to 4.66; p<0.001, and OR 0.60; 95%CI: 0.40 to 0.89; p=0.012, respectively). In conclusions, ACh-provoked diffuse coronary spasm was frequently observed in female VSA patients without severe coronary organic stenosis. These results suggested that angiographic subtypes of ACh-provoked coronary spasm might have different clinical features in VSA patients, indicating the necessity of medical treatment suitable for each subtype of the ACh-provoked coronary spasm.
Abstract 9699: Short Sleep Duration and Glycemic Control Have Synergic Effect on Cardiovascular Events in Hypertensive Patients
Authors: Eguchi Kazuo , Hoshide Satoshi , Ishikawa Shizukiyo , Shimada Kazuyuki , Kario Kazuomi
Published: April 2024

Backgrounds:
Short duration of sleep is associated with increased prevalence of diabetes. We tested the hypothesis that short sleep duration is not only a risk of diabetes, but the combination of these is associated with increased risk of incident cardiovascular disease (CVD).

Methods:
We analyzed 1255 hypertensives who performed ambulatory BP monitoring (ABPM). The mean age was 70.4 ± 9.9 years, and they were followed for 50 ± 23 months. Sleep duration was evaluated by self-report. Diabetes was defined by a history or taking diabetic medications. Short sleep duration was defined as the 20th percentile of the whole population (<7.5hrs).
Hard
CVD event was defined as either myocardial infarction, stroke, or sudden cardiac death; and
All
CVD event was defined as Hard CVD events plus angina, heart failure and end stage renal disease. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) controlling for significant covariates.

Results:
There were 299 diabetic and 956 non-diabetic subjects. The sleep duration was significantly shorter in diabetics than in non-diabetics (8.3±1.4 vs. 8.5±1.4, P=0.005). There were a total of 99 Hard CVD events and 123 All CVD events. When the subjects were divided by 4 categories: Diabetes+Short sleep (n=94); Diabetes+ Long sleep (n=205); Non-diabetes+Short sleep (n=257); Non-diabetes+Long sleep (n=699), the group with Diabetes+Short sleep had significantly higher incidence of Hard CVD events (HR=2.27, 95%CI=1.17-4.42, P=0.015) and All CVD events (HR=2.47, 1.37-4.43, P=0.003) compared with the group with Non-diabetes+Long sleep independent of age, sex, BMI, creatinine, and 24-h SBP. Although there was no interactions between diabetes and short duration of sleep on the impact of CVD events, a subanalysis of diabetic subjects (N=203) have shown that there were significant interactions between the sleep duration and average hemoglobin A1c levels on the impact of Hard and All CVD events.

Conclusion:
The combination of diabetes and short duration of sleep was associated with higher risk of incident cardiovascular disease (CVD) than those without. Worse glycemic control along with short sleep duration had a tendency to act synergistically as risks of future cardiovascular events.
Abstract 9732: Mitral Annular Calcification and Incident Embolic Stroke in Treated Hypertensive Patients: The LIFE Echo-Substudy
Authors: De Marco Marina , De Simone Giovanni , Gerdts Eva , Casalnuovo Giuseppina , Migliore Teresa , Wachtell Kris , Boman Kurt , Dahlöf Bjorn , Deveraux Richard B
Published: April 2024

Background:
Mitral anular calcification (MAC) is not considered as a substantial echocardiographic finding and is often neglected in routine reports. However, MAC has been associated with increased risk of embolic stroke in the general population. Whether MAC also predicts incident embolic stroke in treated hypertensive patients with LV hypertrophy is unclear.

Methods:
Baseline clinical and echocardiographic parameters were assessed in 945 hypertensive patients with ECG left ventricular hypertrophy (LVH) participating in the LIFE echo-substudy (66 ±7 years, 42% women, 11% diabetes). Fifteen participants were excluded because of aortic stenosis and 1 because of mitral stenosis.

Results:
At the baseline echocardiogram, MAC was found in 48% of the study population. Patients with MAC were older (67±7 versus 64±7 years), had higher systolic blood pressure (176±22 versus 171±20 mmHg), heart rate (69±12 versus 67±12 bpm ) left atrial diameter (4.1±0.5 versus 3.8±0.5 cm) and LV mass index (58 ±13 versus 54±12 g/m 2.7 ) and included more women (47% versus 36%), and more patients with diabetes (13% versus 9%) and albuminuria (29% versus 22%, all p<0.01). Over a mean follow-up of 4.8 years, 56 participants (6%) had an embolic stroke. Risk of incident embolic stroke was significantly associated with presence of baseline MAC (log Rank=11, p=0.001). In multivariate Cox- regression analysis, baseline MAC was associated with 2 -fold increased risk of embolic stroke (HR=1.99, CI95%:1.08-3.67,p=0.03), independently of age, gender, baseline systolic BP, heart rate, presence of diabetes, baseline LV mass index, left atrial diameter, albuminuria, prevalent and/or incident atrial fibrillation and randomized antihypertensive treatment (atenolol/losartan).

Conclusions:
In a population of treated hypertensive patients with ECG LVH, MAC was frequently present and was associated with increased risk for incident embolic stroke, independent of other established risk factors.
Abstract 9749: Impact of QRS Duration and Morphology on The Risk of Sudden Cardiac Death in Asymptomatic Patients with Aortic Stenosis: The Simvastatin and Ezetimibe in Aortic Stenosis Study
Authors: Greve Anders M , Gerdts Eva , Boman Kurt , Gohlke-Baerwolf Christa , Rossebø Anne B , Devereux Richard B , Køber Lars , Ray Simon , Willenheimer Ronnie , Kristian Wachtell Kristian
Published: April 2024

Background:
QRS duration and morphology are associated with poor prognosis in many different populations, but the predictive value, particularly of the risk of sudden cardiac death (SCD), in asymptomatic patients with aortic stenosis (AS) has not been well studied.

Methods:
Clinical examination, electrocardiography and echocardiography were obtained in 1,873 asymptomatic AS patients randomized to simvastatin/ezetimibe combination
vs.
placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Association of QRS duration, evaluated as a categorical variable of <85 msec
vs.
85-99 msec and ≥100 msec (excluding bundle branch block [BBB]) and QRS morphology in those with BBB, with the risk of cardiovascular morbidity and mortality was assessed by adjusting for biomarkers, clinical- and echocardiographic covariates as well as randomized treatment.

Results:
QRS data were available in 1,542 patients; followed for a mean of 4.3±0.8 years (6,631 patients-years of follow-up). QRS duration was <85 msec in 900 patients (58.4%), 85-99 msec in 396 (25.7%), ≥100 msec without BBB in 144 (9.3%) and 102 (6.6%) had BBB. In multivariable analyses, those with QRS duration ≥100 msec had, compared to those with QRS duration <85 msec, a 4.9-fold higher risk of sudden cardiac death (95% confidence interval [CI], 1.4 to 16.9, p=0.01) and a 2.7-fold higher risk of cardiovascular death (CI, 1.3 to 5.8, p=0.01). In univariate analyses, left BBB (n=43) was, compared to QRS duration <85 msec, associated with a 3.8-fold higher risk heart failure and right BBB combined with left anterior fascicular block (n=20) with a 4.6-fold higher risk of myocardial infarction (both p<0.05).

Conclusion:
QRS duration and morphology in asymptomatic patients with AS are independently associated with poor prognosis, particularly the risk of SCD.

Figure
:

Incidence of Sudden Cardiac Death According to Baseline QRS Duration and Morphology: During 4.3 Years of Follow-Up.
Abstract 9791: Sex Disparities in Implantable Cardioverter Defibrillator (ICD) Outcomes: Findings From the Ontario ICD Database
Authors: MacFadden Derek R , Crystal Eugene , Krahn Andrew D , Mangat Iqwal , Healey Jeffrey S , Dorian Paul , Khaykin Yaariv , Birnie David , Simpson Christopher S , Pinter Arnold , Calzavara Andrew J , Tu Jack V , Lee Douglas S
Published: April 2024

BACKGROUND:
Sex disparities may exist in decisions to implant an ICD, complications and patient outcomes, but contributing factors are not fully elucidated. We determined if men and women who were referred or implanted with an ICD differed in their device use, complications, and outcomes.

METHODS:
We examined prospectively-enrolled patients referred for consideration of ICD implantation in Ontario between Feb 2007 to Jul 2010 in the Ontario ICD Database. Patients were followed for 45-day complications, and occurrence of ICD-delivered therapies (i.e., appropriate shock, appropriate therapy, and inappropriate therapy) and death within one-year follow-up. Multivariable-adjusted odds ratios (aOR) and hazard ratios (aHR) > 1.0 signified increased likelihood of implantation, complications, ICD-delivered therapies, or death in women.

RESULTS:
Of 6021 patients (4733 men) referred for ICD implantation, 1155 women (89.7%) and 4294 men (90.7%) received devices, with an overall aOR of 0.87 (95%CI; 0.69-1.10, p=0.24). Women were significantly more likely than men to have a minor (aOR 1.55; 95%CI; 1.09-2.20, p=0.014), major (aOR 1.78, 95%CI; 1.24-2.58, p=0.002), or any complication (aOR 1.50, 95%CI; 1.12-2.00, p=0.006). Among 5213 persons (4108 men) contributing 3,860 person-years of follow-up, there was a lower likelihood of appropriate ICD-delivered therapies in women. Adjusted HRs were 0.69 (95%CI; 0.51-0.93, p=0.015) for appropriate shock, 0.73 (95%CI; 0.59-0.90, p=0.003) for appropriate ICD-delivered therapy, and 0.97 (95%CI; 0.64-1.55, p=0.885) for inappropriate shock (
Figure
). Mortality did not differ among male and female ICD recipients: aHR=1.00 (95%CI; 0.64-1.55, p=0.988).

CONCLUSIONS:
ICD implantation rates were similar in men and women after referral to an electrophysiologist. Female ICD recipients exhibited higher rates of early complications and were less likely to experience appropriate shocks or antitachycardia therapy than men.
Abstract 9800: Clinical Effects of the Phosphodiesterase Inhibitor K-134 in Peripheral Artery Disease and Claudication
Authors: Hiatt William R , Cooper Leslie T , Morgan Roger E , Brass Eric P
Published: April 2024

Background:
In peripheral artery disease (PAD), claudication limits exercise performance, functional status and quality of life. Phosphodiesterase III inhibitors improve claudication-limited exercise performance in patients with PAD. K-134, a novel phosphodiesterase III inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess safety, quality of life and peak walking time (PWT) on a graded treadmill with cilostazol as an active comparator.

Design:
Patients with PAD were randomized to receive placebo (N = 87), K-134 at a dose of 25 mg (N = 42), 50 mg (N = 85) or 100 mg (N = 84), or cilostazol at a dose of 100 mg (N = 89), each given twice daily for 26 weeks. A Data Safety Monitoring Board (DSMB) implemented adaptive design was used to allow early discontinuation of unsafe or minimally informative K-134 arms. Interim safety assessments at 2 weeks included dosing of study medication at the study site followed by measurements of postural vital signs and symptoms, and at 4 weeks with a treadmill test at peak drug concentration to evaluate for ischemia or arrhythmias.

Results:
Based on prospectively defined adaptive criteria, the 25 mg K-134 arm was discontinued as the 50 mg and 100 mg doses were adequately tolerated, had no unanticipated safety signals, and were thus most likely to be informative concerning K-134 in the target population. In the intention-to-treat cohorts at 26 weeks PWT increased by 37% in the 100 mg K-134 arm and 23% on placebo (primary analysis p = 0.089). Using a mixed effects analysis in the entire population, 100 mg K-134 and cilostazol were each superior to placebo in improving PWT. In the per protocol population both K-134 100 mg and cilostazol 100 mg increased PWT as compared with placebo at 14 and 26 weeks. K-134 had tolerability and adverse effect profiles similar to that of cilostazol, with gastrointestinal adverse events, headache and dizziness the most common. Both drugs were associated with an increase in withdrawals prior to study completion due to adverse events as compared with placebo.

Conclusions:
K-134 was generally well tolerated, and at a dose of 100 mg twice daily had a safety profile and effect on treadmill walking performance that was similar to that of cilostazol.
Abstract 9803: Relation of Vascular Growth Factors with CT-Derived Measures of Body Fat Distribution: The Framingham Heart Study
Authors: Kaess Bernhard M , Pedley Alison , Massaro Joseph M , Larson Martin G , Corsini Erin , Hoffmann Udo , Smith Holly M , Sawyer Douglas B , Vasan Ramachandran S , Fox Caroline S
Published: April 2024

Background:
Obesity is associated with cardiometabolic risk. However, the localization of excess body fat impacts on the accompanying morbidity. Given that angiogenesis is a key feature of adipogenesis, and that angiogenic factors correlate with cardiovascular risk, variation in the association of levels of circulating vascular growth factors (and their soluble receptors) with distinct body fat compartments may explain differences in the pathogenicity of regional fat depots.

Methods and Results:
We assessed relationships of four body fat compartments (visceral adipose tissue - VAT, subcutaneous adipose tissue - SAT, thoracic periaortic fat, pericardial fat) derived from computed tomography with serum levels of vascular endothelial growth factor (VEGF), the soluble VEGF receptor (sFlt-1), hepatocyte growth factor (HGF), angiopoietin-2 and its soluble receptor (sTie-2) using multivariable linear regression models in 1806 Framingham Third Generation participants (mean age 44.9 years, 44.5% women). VAT, SAT and periaortic fat were positively associated with VEGF (p=0.004, p<0.0001 and p=0.03, respectively). HGF was positively associated with all assessed fat depots (all p<0.0001). VAT and periaortic fat were weakly associated with sTie-2 (p=0.01 and p=0.03). For HGF, we observed effect modification by sex: associations of VAT, pericardial and periaortic fat with HGF were stronger in women than in men; in women, higher VAT and higher periaortic fat were jointly associated with higher HGF concentrations (p=0.02 and p=0.05, respectively). In women within the highest tertile of VAT, HGF levels increased with higher periaortic fat (p=0.0005;
Figure
).

Conclusions:
We observed associations of several body fat compartments with circulating VEGF and HGF levels. In women, high VAT and high periaortic fat were jointly associated with greater HGF levels. Whether this finding will translate to elevated morbidity in this group warrants further evaluation.
Abstract 9832: Individualized Patient Education Program for Prevention of Venous Thromboembolism in Hospitalized Medical Patients
Authors: Piazza Gregory , Nguyen Thanh N , Morrison Ruth , Cios Deborah , Hohlfelder Benjamin , Fanikos John , Goldhaber Samuel Z
Published: April 2024

Introduction:
Up to 15% of clinician-ordered doses of injectable prophylactic unfractionated or low-molecular weight heparin to prevent venous thromboembolism (VTE) are not administered. Patient refusal accounts for nearly 50% of these omitted doses.

Hypothesis:
We hypothesized that a pharmacist-led individualized patient education program will improve medication adherence to clinician-ordered doses of injectable prophylactic anticoagulation.

Methods:
Using our hospital's Electronic Health Record, we identified 528 hospitalized medical patients who were ordered for injectable pharmacological VTE prophylaxis. We evaluated the impact of pharmacist-led individualized patient education sessions, conducted within 24 hours of the initial order for prophylactic anticoagulation, on medication adherence (defined as the ratio of doses administered to doses scheduled).

Results:
Unfractionated heparin was the most frequent clinician-ordered injectable prophylactic anticoagulant (55%) followed by dalteparin (45%). Individualized patient education sessions were conducted within 24 hours of the first dose of prophylactic anticoagulation in 99% of patients. The patient education program improved adherence to clinician-ordered pharmacological VTE prophylaxis from 89.9% in our historical cohort to 94.4% (p<0.0001). The proportion of patients receiving 100% of scheduled doses of pharmacological prophylaxis increased from 82.8% to 91.9% (p=0.001). Patient refusal as a reason for omitted doses decreased from 43.7% to 29.3% after the patient education program (p=0.001).

Conclusion:
Pharmacist-led individualized patient education sessions improved medication adherence to clinician-ordered pharmacological VTE prophylaxis and reduced patient refusal as a cause of omitted doses. Efforts to enhance VTE prevention among hospitalized medical patients should focus on patient education to improve adherence to pharmacological VTE prophylaxis.
Abstract 9907: Epac Activation Protects Heart From Interleukin-6-Induced Cardiac Dysfunction by Inhibiting Stat/iNOS Signaling
Authors: Okumura Satoshi , Jin Meihua , Kawamata Fumika , Jin Hui-Ling , Cai Wenqian , Bai Yunzhe , Suita Kenji , Hidaka Yuko , Tsunematsu Takashi , Ishikawa Yoshihiro
Published: April 2024

Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine has been traditionally understood as PKA-mediated enforcement of cardiac contractility. We hypothesized that Epac (
e
xchange
p
rotein
a
ctivated by
c
yclic AMP), a new target of cAMP signaling that functions independently of PKA, also plays a key role. Activation of Epac with 8-(4-chlorophenylthio)-2’-O-Me-cAMP-AM (8-CPT-AM) (10μM) for 5 hours, an Epac-selective cAMP analogue, significantly attenuated the inhibitory effect of interleukin-6 (30ng/ml) on increase of intracellular Ca
2+
concentration in response to β-adrenergic stimulation with isoproterenol (ISO:10
-5
M) (8-CPT-AM:(-)vs.(+) 3597±306 vs. 4780±186nM, P<0.05, n=31-64 cells) and contractility as evaluated by cell shortening in response to isoproterenol (10
-5
M) in cardiac myocyte (8-CPT-AM:(-) vs.(+) 13.6±0.8 vs. 24.0±1.3%, P<0.01, n=24-27 cells). These effects were mediated through inhibition of STAT3 phosphorylation (8-CPT-AM:(-)vs.(+) 100±4.6 vs. 43±11.5%, P<0.01, n=6) and subsequent induction of inducible nitric oxide synthase (iNOS) protein in cardiac myocytes (8-CPT-AM(-)vs.(+) 100±10.2 vs. 42±4.0%, P<0.01, n=4). Lipopolysaccharide injection induced cytokine release and severe cardiac dysfunction in mouse. In mouse overexpressing Epac1 in the heart, however, the magnitude of such dysfunction was significantly smaller (NTG vs. TG 36±2.4 vs. 19±2.1%, P<0.01, n=15-16). Epac1 overexpression decreased phosphorylation of STAT3 (NTG vs. TG 100±11 vs. 71±6%, P<0.05, n=7) through the increased SOCS3 overexpression (NTG vs. TG 100±12.8 vs. 142±6.4, P<0.05, n=4-7) and subsequent inhibition of iNOS expression (NTG vs. TG 100±11 vs. 66+8%, n=4, P<0.05) in the heart. Activation of the cAMP/Epac pathway protected the heart against cytokine-induced cardiac dysfunction, suggesting a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac1 and its downstream pathway may be a novel target for treating cardiac dysfunction in endotoxemia.
Abstract 9912: The Activation of Natural Killer T Cells Ameliorates Myocardial Ischemia Reperfusion Injury in Mice
Authors: Homma Tsuneaki , Kinugawa Shintaro , Yokota Takashi , Takahashi Masashige , Fukushima Arata , Suga Tadashi , Takada Shingo , Masaki Yoshihiro , Kadoguchi Tomoyasu , Ono Taisuke , Sobirin Mochamad A , Tsutsui Hiroyuki
Published: April 2024

Background
Natural killer T (NKT) cells play an important role in tissue inflammation in various diseases due to the capacity to produce inflammatory cytokines and orchestrate tissue inflammation. It has been reported that preactivation of NKT cells with α-galactosylceramide (α-GC) protects against hepatic ischemia reperfusion injury. However no previous studies have examined the pathophysiological role of NKT cells in myocardial ischemia reperfusion injury.

Methods
A 45 minute occlusion of the left coronary artery followed by 24 hours reperfusion (Ischemia/Reperfusion; I/R) or sham operation was performed in male C57BL/6J mice. I/R mice received the single injection of either αGC (100μg/kg body weight, I/R+αGC, n=14), which specifically activates NKT cells, or vehicle (I/R+vehicle, n=16) 30 minutes before reperfusion. Infiltration of inflammatory cells was assessed by immunohistochemical staining and gene expression of inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were quantified by RT-PCR in the left ventricle.

Results
Hemodynamics such as heart rate and blood pressure were not affected by αGC. The serum and myocardial gene expression levels of IFN-γ did not differ between sham and I/R+vehicle, and they were significantly increased in I/R+αGC in consistent with the activation of NKT cells. Infarct size was significantly smaller in I/R+αGC than I/R+vehicle (infarct size/area at risk: 37.8±2.7 vs 47.1±2.5 %,
P
<0.05), with no significant changes in area at risk (area at risk/left ventricle: 58.5±2.3 vs 58.9±2.7 %,
P
=NS). Serum Troponin-I was also lowered in I/R+αGC (5.8±0.8 vs 8.7±0.7 ng/ml,
P
<0.05). The number of infiltrating CD3 positive cells was lower in I/R+αGC (13.7±2.6 vs 36.3±7.6 cells/HPF,
P
<0.05). In parallel, mRNA expression of TNF-α and IL-1β were lower in I/R+αGC compared to I/R+vehicle (relative value of sham+vehicle: TNF-α 5.8±0.9 vs 11.8±1.9,
P
<0.05 and IL-1β 5.3±1.6 vs 30.0±7.8,
P
<0.05).

Conclusions
The activation of NKT cells ameliorated myocardial ischemia reperfusion injury in mice possibly through the inhibition of inflammatory cell infiltration and inflammatory cytokine expression within the heart.
Abstract 9917: The Site of Greatest Vulnerability is Most Often Located Proximally to the Site of Most Severe Narrowing:
A Virtual Histology Intravascular Ultrasound Study
Authors: de Graaf Michiel A , van Velzen Joella E , de Graaf Fleur R , Dijkstra Jouke , Bax Jeroen J , Reiber Johan H , Schalij Martin J , van der Wall Ernst E , Jukema J. W
Published: April 2024

Introduction:
Previous angiographic studies have shown that almost two-thirds of vulnerable plaques are located in non-obstructive lesions. However, the spatial relationship between the location of most severe narrowing and vulnerable rupture sites has not been fully elucidated. Probably, the site of greatest vulnerability is not always identical to the site of most severe stenosis. Therefore, the aim of the present study was to assess the spatial relationship between the location of the site of greatest vulnerability and the location of most severe narrowing with VH IVUS.

Methods:
Overall, 77 patients (139 vessels) underwent VH IVUS. The site of greatest vulnerability was defined as the cross-section with the largest necrotic core area per vessel, the maximum necrotic core (Max NC) site. The site of most severe narrowing was defined as the minimum lumen area (MLA). Per vessel the distance from both the Max NC site and MLA site to the origo of the coronary artery was evaluated. In addition, the presence of a thin cap fibroatheroma (TCFA) was assessed.

Results:
The mean difference (mm) between the MLA site and Max NC site was 10.8±20.6mm (P<0.001). Interestingly, the Max NC site was located at the MLA site in 7 vessels (5%) and proximally to the MLA site in 92 vessels (66%). Besides, a higher % of TCFA was demonstrated at the Max NC site as compared to the MLA site (24% versus 9%, P<0.001).

Conclusion:
The present findings demonstrate that the site of greatest vulnerability is rarely at the site of most severe narrowing. Most often, the site of greatest vulnerability is located proximally to the site of most severe narrowing. Furthermore a higher percentage of TCFA (plaque phenotype with high-risk of rupture) was demonstrated at the site of greatest vulnerability.
Figure 1
Difference in distance (mm) and distribution between Max NC site and MLA site. In the majority of vessels the site of Max NC is located proximal to site of MLA.
Abstract 9950: Altered Expression of Trpv1 and Sensitivity to Capsaicin in Aortic Baroreceptor Neurons in Diabetic Rats
Authors: Zhang Qi , Tan Yingying
Published: April 2024

It has been well documented that diabetes mellitus is associated with cardiovascular autonomic neuropathy including dysfunction of arterial baroreflex. The mechanisms underlying diabetes-induced baroreflex dysfunction remain poorly understood. Previous studies demonstrate an important role of transient receptor potential vanilloid 1 (TRPV1) receptor in painful neuropathy. Here we investigated the function and expression of TRPV1 in aortic baroreceptor (AB) neurons isolated from streptozotocin-induced diabetic rats between 4 and 8 weeks after onset of diabetes. AB neurons in nodose ganglion were retrograde-labeled by a transported fluorescent dye, Dil. Using the whole-cell patch clamp technique, we found that the inward current activated by the application of capsaicin (1 µM) was significantly smaller in AB neurons from diabetic rats compared with controls. The mean peak current density of capsaicin-induced currents was 145.7 ± 24.7 pA/pF (n = 16) in diabetic neurons and 269.3 ± 31.8 pA/pF (n =15) in controls, respectively. The duration of inward current was decreased 51% in diabetic rats compared with the control group. These evoked currents were completely blocked by the capsaicin antagonist capsazepine. In addition, capsaicin-induced desensitization of TRPV1 was up-regulated, whereas TRPV1 re-sensitization was down-regulated in AB neurons from diabetic rats. Immunofluorescence staining studies demonstrated that the percentage of TRPV1-positive neurons was 50.2 ± 5.0% in control rats and 38.2 ± 1.9% in diabetic rats, respectively. This reduction in TRPV1-positive neurons in AB neurons in diabetic rats was significant (n = 11, p < 0.01). These results suggest that reduced expression and function of TRPV1 are involved in the attenuation of baroreceptor neuron excitability, which subsequently contributes to the impairment of baroreflex in diabetes state.
Abstract 9991: Mesenchymal Stem Cells Overexpressing CXCR4 (MSC
CR4
) Promote Neovascularization as Revealed by Suicide Gene Approach
Authors: Liang Jialiang , Huang Wei , Zhao Tiemin , Ashraf Atif , Xu Meifeng , Millard Ronald W , Wary Kishore K , Wang Yigang
Published: April 2024

Background:
Our previous studies indicated that MSC
CR4
improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSC
CR4
in neovascularization of infarcted myocardium using a suicide gene approach.

Methods:
A regenerating recombinant lentivirus (Lentivector Expression System) was devised to deliver the CXCR4, herpes simplex virus-thymidine kinase (TK) driven by an endothelial-specific promoter of VE-cadherin (pCDH-TK), or without the promoter as negative control (pCDH-null) (Fig. 1A). Ganciclovir (GCV) induced suicide in cells expressing both TK and VE-cadherin.
In vitro
, pCDH-TK or pCDH-null was transduced into EC (EC
TK
or EC
null
) and cells were treated with vehicle (VEH) or GCV (100µM) for 7 days.
In vivo
, female rats with myocardial infarction (MI) after permanent LAD ligation were transplanted with either male ordinary MSC (MSC
Ord
), MSC (MSC
Null
), MSC
CR4
or MSC
CR4
transduced with pCDH-TK (MSC
CR4
-TK). Rats then received VEH or GCV (100mg/kg daily for 7 days) by IP injection before euthanasia.

Results:
GCV significantly decreased the number of EC
TK
but had no effect in EC
null
. Absent GCV, TK expression had no effect on EC growth (Fig. 1B & C).
In vivo:
GCV reduced significantly neovascularization in post-MI hearts transplanted with MSC
CR4
-TK. New vessel formation was not affected either after exposure to VEH or GCV in the absence of pCDH-TK. Y-chromosome positive nuclei were observed in newly formed vessels (Fig. 1D-H).

Conclusion:
MSC
CR4
plays an important role in neovascularization during cardiac repair after infarction.
Abstract 18238: Transition from Vitamin-K-antagonists to New Oral Anticoagulants in Daily Care - First Results of the Prospective
NOAC Registry
(NCT 01588119)
Authors: Koehler Christina , Werth Sebastian , Gelbricht Vera , Hänsel Ulrike , Tittl Luise , Beyer-Westendorf Ines , Schreier Thomas , Beyer-Westendorf Jan
Published: April 2024

Background:

New oral anticoagulants (NOAC) have been approved in a number of countries for long-term anticoagulation in atrial fibrillation (AF) and venous thromboembolism (VTE). Currently, many patients are switched from Vitamin-K antagonists (VKA) to NOAC. We evaluated the transition process (time gap between last intake of VKA, last INR sampling and first intake of NOAC) in unselected patients from daily care.

Patients and methods:

A network of 115 physicians from private practice and hospitals enrol patients in the NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. Patients are prospectively followed by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data.

Results:
Until June 6
th
2012, 683 patients were registered. Of the 266 patients switched from VKA, data on the transition process were available in 213 patients (70.0% AF, 30.0% VTE). Of these, only 104 patients (48.8%) had a recorded INR measurement at the end or within 7 days before the end of VKA treatment (mean INR 2.4 for all, 2.6 in AF and 2.1 in VTE patients; table 1). In patients with INR tests, time between last INR and start of NOAC was around 3 days (5 days in AF and 2 days in VTE patients). For all patients, time between last VKA and start NOAC was around 7 days (8 days in AF; 4 days in VTE patients).

Conclusion:
In unselected patients in daily care, only 50% of patients have a documented INR test before NOAC is started. Despite documented INR values in the lower therapeutic range, physicians are reluctant to start NOAC therapy immediately and allow for another 2 to 5 days before NOAC is started. However, no major vascular events or major bleedings were observed in VKA transition patients at day 30, indicating that this procedure is safe.
Abstract 18260: Cyclic GMP Enhancing Therapy Promotes Titin Phosphorylation and Corrects High Cardiomyocyte Passive Stiffness in Diastolic Heart Failure
Authors: Hamdani Nazha , Kalkidan Bishu G , van der Velden Jolanda , Stienen Ger J , Redfield Margaret M , Linke Wolfgang A
Published: April 2024

Myofiber passive stiffness is lowered by phosphorylation of the giant sarcomeric protein titin, with beneficial effects on diastolic function. Titin can be phosphorylated by cGMP-activated protein kinase (PK)G, a pathway stimulated by B-type natriuretic peptide (BNP) or PDE-5A inhibitor (sildenafil). Whether titin phosphorylation and stiffness are affected by PKG activation in vivo had not been studied. Here we examined how dogs with experimental hypertension and diastolic dysfunction, induced by renal wrapping, respond to treatment with β-blockers, sildenafil, and BNP, in terms of altered titin phosphorylation and passive stiffness. Isolated permeabilized cardiomyocytes from left ventricular (LV) biopsies untreated (n=5), treated with β-blockers (n=7), followed by sildenafil (n=7) and BNP (n=7) were attached to a force transducer and the passive length tension relation (F
pas
) was measured between 1.8 and 2.4µm sarcomere length (SL) before and after PKA and PKG administration. We also assessed phosphorylation of myofilament proteins including titin, cMyBPC, desmin, cTnT, cTnI and MLC2 by gel electrophoresis (SYPRO Ruby and ProQ Diamond stain) and expression of titin PEVK, phospho-PEVK, cTnI, phospho-cTnI (at Ser 23/24), PKCα and phospho-PKCα by Western blotting. Compared to untreated cardiomyocytes, F
pas
was unaltered with β-blocker therapy, but significantly reduced with sildenafil; with BNP F
pas
did not change further. Ex-vivo administration of PKG lowered F
pas
of untreated and β-blocker cardiomyocytes to the levels measured in sildenafil and BNP samples, and additional administration of PKA did not further change F
pas
. Total titin phosphorylation was low in untreated samples and with β-blockade, but significantly increased with sildenafil and BNP. Total cTnI phosphorylation and phospho-cTnI at Ser 23/24 were low in untreated compared to treated samples but were similar between β-blocker, sildenafil and BNP groups. Phospho-PEVK and phospho-PKCα were high in untreated samples and with β-blockade, but reduced with sildenafil and BNP. Acute cGMP enhancing therapy with sildenafil and BNP improves LV diastolic function through correction of a titin phosphorylation deficit, thereby reducing cardiomyocyte passive stiffness.