bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10200: Translational Research of Novel Angiogenic Peptide for Wound Healing Drug; From Discovery to Clinical Trial
Authors: Nakagami Hironori , Morishita Ryuichi
Published: July 2021

We developed a novel cationic peptide, AG30/5C, with angiogenic properties. Since it has both angiogenic and antimicrobial actions, it might be a candidate peptide for wound healing drug. We conducted a physician-initiated clinical trial of AG30/5C for severe skin ulcer in patients as an open label study. The primary outcome is safety because it is first in human trial on early stage. AG30/5C was administered with patients with skin ulcer twice per day for two weeks, and ulcer size and Methicillin-Resistant Staphylococcus Aureus amount was quantified as a secondary outcome. Two patients was registered until now and the skin ulcer of first patient was completely cured after AG30/5C treatment. The Methicillin-Resistant Staphylococcus Aureus amount of both patients was decreased during the AG30/5C treatment. This result suggests the potential of AG30/5C as a wound healing drug, however, improvement of stability and cost efficiency are required toward drug development. Thus, we addressed to the metabolites of AG30/5C which can provide a further optimized compound, SR-0379. SR-0379 also enhanced proliferation, tube formation, migration and contraction on human dermal fibroblast cells via the PI3K-Akt-mTOR pathway through integrin-mediated interactions. We evaluated the effect of SR-0379 on two different would healing model in rats, the full-thickness defects in diabetic condition and an acutely infected wound with the full-thickness defects and inoculation with S aureus. Treatment of SR-0379 significantly accelerated the wound healing compared to that of FGF2. The beneficial effects of SR-0379 on wound healing would be explained by enhanced angiogenesis, granulation tissue formation, proliferation and antimicrobial activity. These results clearly demonstrated that SR-0379 may have a potential for drug development in wound repairing, in especially critical colonization condition. Based on these results, we now conducted the physician-initiated clinical trial for severe skin ulcer in patients as a double blind study.
Abstract 10245: Arterial Stiffness, Central Pulsatile Hemodynamic Load and Orthostatic Hypotension: A Cross-sectional Survey of Community Residents in Chengdu
Authors: Liu Kai , Chen Xiaoping , Wang Si , Wan Shixi , Zhou Yufei , Pan Pei , Wen Bo , Zhang Xin , Liao Hang , Shi Di , Shi Rufeng
Published: July 2021

Introduction:
Orthostatic hypotension (OH) is an independent risk factor for cardiovascular morbidity and often unrecognized in the elderly. The association between measures of central pulsatile hemodynamic load or arterial stiffness with OH is unclear. This study evaluated the usefulness of these indexes to identify OH.

Hypothesis:
We hypothesize that direct measures of central pulsatile hemodynamic load (e.g. central systolic blood pressure) and arterial stiffness (pulse wave velocity) both associated with OH. And Measures of central pulsatile hemodynamic load may represent a better indicator of OH.

Methods:
A sample of 1099 participants was recruited from the general population who attended health check-ups. Questionnaire, physical examination and laboratory tests were performance by a standard protocol. To assess the correlation between central hemodynamic indexes and the probability of OH, multiple logistic regression analysis was used to estimate the odds ratio in different models, and the discriminatory power of hemodynamic indexes for OH was assessed by the area under the receiver operating curve (ROC).

Results:
The prevalence of OH in this population was 5.6 %. Compared with those without OH, OH subjects had a higher age, SBP in sitting position, BP in supine position, brachial-ankle PWV (BaPWV) and central systolic blood pressure (CSBP) (all P<0.05). After adjusting for potential confounders, both CSBP (OR=1.039, 95%CI: 1.016-1.062, P=0.001) and BaPWV (OR=1.259, 95%CI: 1.130-1.402, P< 0.001) were significantly positive correlated with OH. However, in subgroup analysis, CSBP (OR=1.017, 95%CI: 0.985-1.050, P=0.310) was insignificantly associated with OH in non hypertension subgroup. In addition, BaPWV seemed to be a better discriminatory power than CSBP in both two subgroups (BaPWVAUC-CSBPAUC =0.127, 95%CI: 0.020-0.233, P=0.02 in non hypertension group; BaPWVAUC-CSBPAUC =0.118, 95%CI: -0.030-0.267, P=0.117 in hypertension group).

Conclusion:
BaPWV appears to be a better indicator of OH in the elderly. If a patient’s BaPWV is greater than 18m/s, Clinicians should better to carry out supine to standing blood pressures measurement in routine clinical practice.
Abstract 10281: Cangrelor’s Anti-Infarct Effect Requires Phosphorylation of Sphingosine in Platelets: The Missing Link
Authors: Cohen Michael V , Yang Xi-Ming , White James , Yellon Derek , Bell Robert , Downey James M
Published: July 2021

Patients with myocardial infarction routinely receive a platelet P2Y12 receptor antagonist prior to percutaneous coronary intervention. In monkeys, rabbits, and rats P2Y12 antagonists act as potent postconditioning-mimetics. Unlike ischemic postconditioning, however, the P2Y12 antagonist cangrelor could not reduce infarct size in Krebs buffer-perfused hearts. We tested whether platelets were required for protection from cangrelor. Rats were treated with intraperitoneal placebo or anti-rat thrombocyte serum (ARTS), 0.5ml, which decreased platelet counts by at least 96%. After 24h the heart was exposed and left coronary artery occluded for 30min and reperfused for 2h. Risk zone and infarct size were measured. In placebo rats infarct size averaged 45.3±1.2% of risk zone, while an intravenous bolus of cangrelor, 60μg/kg, 10 min before reperfusion followed by infusion of 6μg/kg/min decreased infarction to 25.0±1.8% (p<0.001). ARTS alone had no effect on infarct size (50.5±3.7%). However, ARTS blocked cangrelor’s protective effect (48.4±3.4% infarction). Hence cangrelor’s cardioprotective effect depends on platelets. But how can cangrelor cause platelets to trigger postconditioning’s protective signaling? Activated platelets release sphingosine -1 phosphate (S1P), a known trigger for conditioning. Some of the S1P from platelets comes from a sphingomyelinase that is recruited during activation and catabolizes membrane sphingomyelin to sphingosine (sph) which is quickly phosphorylated by sph kinases. We blocked sph kinase with intravenous N-N-dimethylsphingosine (DMS), 0.33 mg/kg, administered 15 min after coronary occlusion. DMS alone had no effect on infarction (43.8±2.3%). But it abrogated cangrelor’s protective effect (42.8±2.0%). In the presence of cangrelor platelets can’t aggregate and plug vascular defects caused by ischemic injury. We propose that in cangrelor-treated post-ischemic hearts platelets enter the interstitial space early in reperfusion and release S1P when they contact collagen which postconditions the heart and protects against reperfusion injury. Thus blocking aggregation allows platelets to produce a pharmacological trigger of postconditioning that reduces infarction.
Abstract 10306: Identification and Characterization of Orally Bioavailable Small Molecule Protease Proprotein Convertase Subtilisin-like Kexin Type 9 Inhibitors
(Best of Basic Science Abstract)
Authors: Elshourbagy Nabil A , Meyers Harold V , Mousa Shaker A , Abdel-Meguid Sherin S
Published: July 2021

Intervention with drugs to reduce low density lipoprotein-cholesterol (LDL-C) has proven to decrease mortality and morbidity. Here, we report the development of small molecules that lower LDL-C by targeting the LDL-receptor (LDLR) degradation pathway, which is modulated by the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 is synthesized as a 72-kDa zymogen that undergoes autocatalytic processing between the prodomain and catalytic domain, an important step that is absolutely required for secretion of PCSK9 and its function. Secreted PCSK9 binds to the LDLR and enhances its degradation. We have identified inhibitors of the autocatalytic processing by virtual docking of millions of commercial compounds into the atomic structure of the PCSK9 active site. Top scoring compounds that showed the best fit in the active site were selected for screening. These compounds were tested for their ability to inhibit the autocatalytic processing/secretion of PCSK9. The most potent compounds exhibited a concentration-dependent inhibition of the PCSK9 processing/secretion with IC50’s in the nanomolar range. These compounds were tested for selectivity against other PCSK’s. The data demonstrated that these compounds were selective in that they inhibit PCSK9 processing/secretion without affecting the secretion of other related PCSK’s. Furthermore, these compounds exhibited a 5- to 10-fold LDLR upregulation at 1.6 μM in two recombinant cell-based assays as well as exhibited an increase in the fluorescently labeled DiI-LDL uptake
in situ
in the nanomolar range. In animal studies, intraperitoneal (IP) injection of these compounds administered alone resulted in more than 20% reduction in LDL-C in mice fed a high fat/high cholesterol diet and over 40% reduction in LDL-C if administered in combination with atorvastatin.
In vivo
pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of these compounds demonstrated that they are orally efficacious, with one compound exhibiting 43% oral bioavailability. Thus, identifying small molecule, orally active PCSK9 modulators represents a significant advance and opportunityfor drug development.
Abstract 10390: Impact of Diabetes Mellitus on the Prognosis of Patients With Heart Failure and Preserved Left Ventricle Ejection Fraction: Insights From the TOPCAT Study
Authors: Huynh Thao , Harty Brian , Assmann Susan , O'Meara Eileen , Anand Inder , Fleg Jerome , Claggett Brian , Pitt Bertram , Rouleau Jean ,   The TOPCAT Investigators
Published: July 2021

Background:
The impact of diabetes mellitus (DM) for patients with heart failure and preserved left ventricle ejection fraction (HFpEF) remains unclear. We aimed to determine the impact of DM on the prognosis of patients with DM and HFpEF enrolled in the TOPCAT trial.

Methods:
We classified TOPCAT patients into three groups: insulin-dependent DM (IDDM), non-insulin dependent DM (NIDDM) and non-DM. We investigated the occurrence of a major adverse cardiovascular event (MACE), defined as CV mortality, hospitalization for HF, non-fatal myocardial infarction (MI), non-fatal non-hemorrhagic stroke, or aborted cardiac arrest. Secondary outcomes included the individual components of MACE and all-cause mortality. We used multivariate Cox proportional hazards regression models to evaluate the independent associations of DM on time to MACE.

Results:
There were 1,134 DM patients (439 IDDM and 695 NIDDM) and 2,307 non-DM patients. The IDDM patients were younger and more likely to be male, non-white, and from the Americas. Despite having the highest median left ventricle’s ejection fraction (LVEF) (58%) compared to NIDDM and non-DM patients (57% and 56%, respectively, p=0.007), they were more symptomatic. Forty-eight percent of IDDM patients were of New York Heart Association (NYHA) III/IV functional classes compared to 36% of NIDDM and 29% of non-DM patients (p<0.001). IDDM patients had significantly increased risks for MACE, CV mortality, MI, HF hospitalization, and all-cause mortality when compared to non-DM patients (p-values<0.01). NIDDM patients had similar risks for MACE and the secondary outcomes as the non-DM patients. The effect of diabetes on outcomes was similar between regions.

Conclusion:
Among HFpEF patients, IDDM but not NIDDM was independently associated with increased risks of MACEs. Future research is needed to evaluate whether optimal medications and lifestyle interventions may reduce MACE in these high-risk patients.
Abstract 10436: The Association of Time to First Epinephrine Administration With Neurological Outcomes in Out of hospital Cardiac Arrest in Japan: Sos-kanto 2012 Study Report
Authors: Homma Yosuke , Funakoshi Hiraku , Shiga Takashi , Miyazaki Dai , Yonemoto Naohiro , Tahara Yoshio , Nagao Ken , Yaguchi Arino , Morimura Naoto , Sakurai Atsushi ,   SOS-KANTO 2012 Study Group
Published: July 2021

Introduction:
The clinical effectiveness of the timing of first epinephrine administration (EA) including prehospital setting has not been established, especially in regards to neurological outcomes in patients subsequently receiving intensive care after admission.

Study Objectives:
The aim of this study was to evaluate the effectiveness of time to first EA on neurological outcomes following OHCA.

Methods:
This was a multicenter retrospective cohort study in Japan from January 2012 to March 2013. We used data from the Survey of Survivors after Cardiac Arrest in the Kanto Area in 2012 (SOS-KANTO 2012) database. All adult patients who were registered in this database and were administered epinephrine were included; unwitnessed OHCA and initial asystolic rhythms were excluded.

Collected variables included age, gender, activities of daily living, witnessed status, bystander CPR, first documented rhythm, cause, and intensive care after admission. Multivariate logistic regression was performed to investigate the association between time to first EA and 1) ROSC, 2) 1-month survival, and 3) 1-month favorable neurological outcome.

Results:
Of 16,452 OHCAs, 5,281 met the inclusion criteria (male, 63.1%; mean age, 71.5 years). Mean time between call to first EA is 33.7min. 1,501patients (28.4%) had ROSC. Multivariate logistic regression showed that the earlier the EA, the better chance of ROSC if initial documented rhythm was both VF/VT (adjusted odds ratio [OR] for one minute delay, 0.98; 95% confidence interval [CI], 0.97-0.99) and Asystole/PEA (adjusted OR, 0.97; 95%CI, 0.97-0.98). In contrast, the earlier the EA, the better chance of 1-month survival if initial documented rhythm was only Asystole/PEA (adjusted OR, 0.95; 95%CI, 0.93-0.98). There were no significant differences between early EA and good neurological outcomes (VF/VT, 1.01 [95% CI, 0.97-1.04] and Asystole/PEA, 1.01 [95% CI, 0.96-1.05]).

Conclusions:
If initial documented rhythm was VF/VT, early EA was associated with increased chance of only ROSC. In contrast, early EA was associated with increased chance of ROSC and 1 month survival if initial documented rhythm was Asystole/PEA. Time to first EA was not associated with good neurological outcomes in any initial documented rhythm.
Abstract 10862: The Effects of a New Medication Monitoring Programme on Blood Pressure Control Among Elderly Home Residents With Multiple Medications
Authors: Wong Martin CS , Wang Harry HX , Kwan Mandy WM , Li Shannon TS , Griffiths Sian M
Published: July 2021

Objective:
A high prevalence of hypertension among the elderly has raised public concern in Asia particularly in Hong Kong. It is commonly observed among elderly being prescribed with more than one antihypertensive agent. However, poor adherence can serve as one of the major causes of suboptimal blood pressure (BP) control, and particular in elderly homes where the residents often lack family support. The study aimed to evaluate the effects of a new medication monitoring programme on BP control among elderly home residents with multiple medications.

Methods:
We recruited study subjects from three elderly homes enrolled in a pharmacist-led home-based medication monitoring programme launched by the Hong Kong Pharmaceutical Care Foundation. The programme aimed to optimise drug therapy and achieve better BP control. We used a cluster sampling to recruit elderly people (aged ≥65 years) prescribed with multiple medications, who were then followed up for six months. Subjects in the intervention group received medications under pharmacist-led medication monitoring programme, while the control group received usual care. Intention-to-treat analysis was adopted. Systolic BP and diastolic BP were measured at each 3-monthly follow-up as primary outcomes. Secondary outcomes included healthcare utilisation and staff satisfaction. Repeated measures analysis of variance (RMANOVA) was used to estimate the intervention effect after adjusting for other covariates.

Results:
A total of 290 residents were recruited. The study showed distinct patterns of changes in SBP and DBP between groups. After 6 months, participants in the intervention group (n=200) had an average of 5.16mmHg (p=0.134) and 2.66mmHg (p=0.198) decrease in SBP and DBP, respectively; while the control group (n=90) showed 12.40mmHg (p=0.027) and 6.60mmHg (p=0.061) increase in SBP and DBP, respectively, after adjusting for other covariates.

Conclusions:
Elderly home residents enrolled in this new pharmacist-led home-based medication monitoring programme had better BP parameters, suggesting that future programmes on other cardiovascular disease medications based on similar approach could potentially be effective in achieving favourable outcomes among the elderly population in primary care.
Abstract 10922: Relationship of the AHA Impact Goals (Life’s Simple 7) With Risk of Chronic Kidney Disease: Results From the ARIC Cohort Study
Authors: Rebholz Casey M , Anderson Cheryl A , Grams Morgan E , Bazzano Lydia A , Crews Deidra C , Chang Alex R , Coresh Josef , Appel Lawrence J
Published: July 2021

Introduction:
As part of its 2020 Impact Goals, the AHA developed the Life’s Simple 7 metric for cardiovascular health promotion. The metric consists of ideal categories for smoking, physical activity, diet, body mass index, blood pressure, blood cholesterol, and blood glucose; and its relationship with risk of chronic kidney disease (CKD) is unknown.

Hypothesis:
Ideal levels of health factors and the overall Life’s Simple 7 metric are associated with lower risk of developing CKD.

Methods:
We prospectively analyzed 15,436 Atherosclerosis Risk in Community study participants without CKD at baseline (1987-1989). Ideal levels of health factors were: non-smoker or quit >1 year ago; body mass index <25 kg/m
2
; ≥150 minutes/week of physical activity; dietary pattern which is high in fruits and vegetables, fish, and fiber-rich whole grains, and low in sodium and sugar-sweetened beverages; total cholesterol <200 mg/dL; blood pressure <120/90 mmHg; and blood glucose <100 mg/dL. Incident CKD was defined as development of estimated glomerular filtration rate <60 mL/min/1.73 m
2
accompanied by 25% decline from baseline, hospitalization or death due to CKD, or end-stage renal disease defined by linkage with the U.S. Renal Data System. Cox regression was used to estimate associations between health factors, the overall metric, and CKD risk while adjusting for age, sex, race, and baseline kidney function.

Results:
At baseline, mean age was 54 years, 55% were women, and 26% were African-American. There were 2,861 incident CKD cases over a median follow-up of 22 years. Smoking, body mass index, physical activity, blood pressure, and blood glucose were associated with lower CKD risk (all p≤0.01), but diet and blood cholesterol were not. CKD risk was inversely related to the number of ideal health factors (
Figure
; p-trend<0.001; AUC: 0.7001 vs. 0.6804, p<0.001).

Conclusions:
The AHA Life’s Simple 7 metric, developed to measure and promote cardiovascular health, predicts reduced CKD risk.
Abstract 11009: Serum Cholesterol Efflux Capacity is an Independent Predictor of All-cause and Cardiovascular Mortality in Patients With Coronary Artery Disease
Authors: Liu Chaoqun , Zhang Yuan , Ding Ding , Wang Dongliang , Li Xinrui , Yang Yunou , Li Qing , Zheng Yuanzhu , Ling Wenhua
Published: July 2021

Objective
To investigate the association between serum cholesterol efflux capacity and all-cause and cardiovascular mortality in patients with coronary artery disease.

Design
Prospective cohort study.

Setting
Guangdong Coronary Artery Disease Cohort, established in 2008-2011.

Participants
1 765 patients with coronary artery disease were followed-up for a median of 3.9 years.

Main outcome measures
Primary outcome was the association of baseline serum cholesterol efflux capacity with the risks of all-cause and cardiovascular mortality.

Results:
During 6 778 person-years of follow-up, 170 deaths were registered, 126 of which were caused by cardiovascular diseases. After multivariate adjustment for factors related to cardiovascular diseases, the hazard ratios (95% confidence intervals) across quartiles of serum cholesterol efflux capacity were 1.00, 0.75 (0.51-1.10), 0.51 (0.33-0.81) and 0.43 (0.25-0.73) for all-cause mortality (
P
= 0.003), and 1.00, 0.76 (0.49-1.18), 0.37 (0.21-0.65), and 0.25 (0.12-0.52) for cardiovascular mortality (
P
< 0.001). Adding serum cholesterol efflux capacity to a model containing traditional cardiovascular risk factors significantly increases its discriminatory power and predictive ability for all-cause (area under receiver operating characteristic curve 0.68 versus 0.61,
P
< 0.001; net reclassification improvement 14.5%,
P
= 0.001) and cardiovascular (area under receiver operating characteristic curve 0.71 versus 0.63,
P
< 0.001; net reclassification improvement 18.4%,
P
< 0.001) death, respectively.

Conclusions:
Serum cholesterol efflux capacity may serve as an independent measure for predicting all-cause and cardiovascular mortality in patients with coronary artery disease.
Abstract 11021: Circulating Cardiac Transforming Growth Factor-β is a Principal Determinant in Inducing Myocardial Hypertrophy in Transgenic Mice Overexpressing Exogenous Hepatic Transforming Growth Factor-β
Authors: Khan Shaukat A , Tsuda Takeshi
Published: July 2021

Introduction:
Transforming growth factor (TGF)-β is a potent growth factor that induces myocardial hypertrophy, but an interaction between circulating and myocardial TGF-β has been poorly understood. An extracellular matrix protein, fibulin-2, mediates exogenous TGF-β-induced endogenous TGF-β up-regulation in isolated cardiac fibroblasts.

Hypothesis:
Systemic TGF-β-induced myocardial hypertrophy is mediated primarily by enhanced myocardial TGF-β via paracrine fashion.

Methods:
We created double mutant mice with TGF-β1 over-expressing transgenic mice (TG) and fibulin-2 knockout mice (KO). TG developed myocardial hypertrophy due to excessive circulating hepatic TGF-β. We studied TGF-β dynamics between tissues and circulation during hypertrophic changes.

Results:
TG/WT developed significant myocardial hypertrophy at 8 weeks compared with non-TG (NTG) groups. Hypertrophy in TG/KO was significantly attenuated compared with TG/WT. Myocardial TGF-β mRNA level was significantly up-regulated in TG/WT compared with TG/KO or NGT groups, so was Smad2 activation, but myocardial TGF-β bioactivity was no different among all four groups. Serum carrier-bound TGF-β was significantly higher in TG/WT than in TG/KO or NTG groups, but free unbound TGF-β level was equally elevated in TG groups compared with NTG groups. Thus, hypertrophy in TG/WT may be attributed to increased serum carrier-bound TGF-β levels, not to either myocardial TGF-β activity or serum unbound TGF-β levels. Endogenous TGF-β mRNA level in kidney and liver was equally increased in TG group compared with NTG group, and was comparable in all 4 groups in lung, suggesting fibulin-2 was not involved in TGF-β-induced TGF-β synthesis in kidney, liver, or lung.

Conclusions:
Hepatic TGF-β-induced-myocardial TGF-β up-regulation was mediated by fibulin-2. In TG/WT, up-regulated myocardial TGF-β was mainly secreted into circulation as a soluble carrier-bound form and did not directly induce hypertrophy via paracrine fashion. It is this circulating endogenous myocardial TGF-β rather than transgene-induced hepatic TGF-β that is responsible for myocardial hypertrophy in TG/WT. Heart is a major endocrine organ in secreting circulating endogenous TGF-β in inducing myocardial hypertrophy.
Abstract 11138: Superresolution Studies of Sodium Channels Within Intercalated Disk Microdomains Suggest Novel Arrhythmia Mechanism
Authors: Veeraraghavan Rengasayee , Lin Joyce T , Keener James P , Poelzing Steven , Gourdie Robert G
Published: July 2021

Pore-forming (Nav1.5) and auxiliary (β1; SCN1b) subunits of cardiac sodium channels are enriched at the cardiomyocyte intercalated disk (ID). Mathematical models suggest that this may facilitate conduction via ephaptic mechanisms.

We recently demonstrated Nav1.5 enrichment (gSTED superresolution microscopy) and close membrane apposition (<10 nm; electron microscopy) within the perinexus, a microdomain surrounding connexin43 (Cx43) gap junctions (GJ). These data identified the perinexus as a candidate structure for the cardiac ephapse. Further studies using gSTED and STORM superresolution microscopy revealed Nav1.5 and β1 enrichment within ID regions not containing dense clusters of Cx43 and N-Cadherin. Notably, both were identified within the perinexus: Overall, 22% of Nav1.5 & β1 were located within perinexal regions while only 2 and 5% respectively overlapped with Cx43 clusters. Importantly, acute interstitial edema (AIE) increased intermembrane distance at perinexal, but not at non-perinexal sites in adult guinea pig myocardium. Functionally, this correlated with decreased transverse conduction velocity (CV-T; 15.2±0.3 vs. 19.6±0.1cm/s) and increased anisotropic ratio (AR; 3.0±0.2 vs. 2.8±0.1) relative to control, in perfused guinea pig ventricles. Nav1.5 blockade (0.5 μM flecainide) by itself decreased CV (18%) without changing AR. However, Nav1.5 inhibition during AIE preferentially decreased CV-T (13.0±0.6cm/s), increased AR (3.3±0.2) and increased spontaneous arrhythmias (7/9 vs. 4/11) compared to AIE alone. Notably, only a computer model including ephaptic coupling and the ID localization of Nav1.5 could recapitulate these results. Next we investigated the role of β1 in ephaptic coupling: Electrical cell-substrate impedance spectroscopy of 1610 cells heterologously overexpressing β1 revealed 3-fold higher paracellular resistance relative to native 1610 cells.

These data along with the known cell adhesion function of β1 in neural tissue suggest that β1-mediated adhesion may facilitate close membrane apposition within the perinexus. Taken together, our results identify β1-mediated adhesion as a novel determinant of anisotropic conduction and potential antiarrhythmic target.
Abstract 11339: Relationship of LPA Single Nucleotide Polymorphisms With Apolipoprotein (a) Isoforms and Biomarkers of Oxidized Lipoproteins in African-Americans, Caucasians and Hispanics: Results From the DALLAS Heart Study
Authors: Tsimikas Sotirios , Xing Chao , Choi Yun-Seok , Ku Hung-Chih , Witztum Joseph L
Published: July 2021

Background:
Oxidized phospholipids (OxPL) measured on apolipoprotein B-100 particles (OxPL-apoB) are a measure of the pro-inflammatory activity of Lp(a). Lp(a) in plasma is genetically determined by variability in kringle IV (KIV) repeats and single nucleotide polymorphisms (SNPs) in the LPA gene, is causally related to cardiovascular disease (CVD) and has become a target of therapy.

Methods and Results:
OxPL-apoB IgG and IgM autoantibodies to oxidized LDL and apoB-immune complexes, KIV repeats of the major apolipoprotein (a) isoform, LPA snps rs3798220, rs10455872 and rs9457951 were measured in 3454 subjects (1798 African-Americans, 1032 Caucasian and 576 Hispanic) subjects enrolled in the Dallas Heart Study (Table). All 3 snps were highly correlated with the number of KIV repeats in African-Americans but only rs3798220 and rs10455872 were correlated with KIV repeats in Caucasians or Hispanics. rs3798220 and rs10455872 demonstrated strong correlations with Lp(a) and OxPL-apoB levels in subjects with low numbers of KIV repeats, whereas rs9457951 showed similar associations only in African-Americans. None of the LPA snps correlated with the other biomarkers of oxidation.

Conclusion:
Significant racial differences exist among LPA SNPs and their relationship to Lp(a), apolipoprotein (a) isoforms and OxPL-apoB. These findings may provide insights into the clinical variability of Lp(a)-mediated risk in different racial groups and suggests novel avenues of investigation and therapeutic potential in mitigating the CVD risk of Lp(a) and OxPL-apoB.
Abstract 11415: Enhancing Direct Cardiac Reprogramming Efficiency Using Small Molecules
Authors: Mohamed Tamer M , Stone Nicole , Berry Emily , Wang Haixia , Ding Sheng , Srivastava Deepak
Published: July 2021

The ability to directly trans-differentiate fibroblasts into cardiomyocytes through overexpression of three core transcription factors, Gata4, Mef2C &TBX5 (GMT), has been demonstrated by our group and others. Direct cardiac reprogramming has great potential to treat heart failure. However, clinical application remains limited due to inefficiencies in the reprogramming process and immaturity of the differentiated cardiomyocytes. In the current work, using a chemical approach we aim to increase the efficiency and the maturation of these directly reprogrammed cardiomyocytes.

We have optimized a high-throughput screening method in 384-well plates using an alpha-MHC-GFP reporter to detect cardiac reprogramming in mouse cardiac fibroblasts. We screened 5500 compounds and identified 20 hits which have increased the reprogramming efficiency by 2-6 fold compared to controls. Among these top hits, 4 TGF-β inhibitors (DS 1-4) and 4 WNT inhibitors (DS 5-8) enhanced direct cardiac reprogramming. Further in depth investigations showed that the combination of the TGF-β inhibitor DS1 and the WNT inhibitor DS5 increased reprogramming efficiency 7 fold when added to the GMT-overexpressing fibroblasts on the first day of reprogramming. This combination of small molecules also enhanced the maturation of the reprogrammed cells, as we observed beating cells after only 1 week of reprogramming compared to 6–8 weeks without the small molecules. Activation of canonical WNT signaling or TGF-β signaling significantly abrogates the improvement in cardiac reprogramming by DS1 and DS5. These results indicate the specificity of the action of these inhibitors through the canonical WNT and TGF-β pathways. In a translational effort, we injected DS1, 2 and 5 intraperitoneally in mice for 2 weeks in combination with GMT following myocardial infarction (MI) and found a significant improvement in cardiac function as represented by an ejection fraction of 39.11% ±1.2% in the GMT + compounds group vs. 28.44% ± 3.98% in the GMT only group (p<0.05), 6 weeks after MI compared to an ejection fraction of 22.72% in the control untreated group.

In conclusion, small molecules, especially the TGF-β inhibitors and WNT inhibitors, greatly enhanced direct reprogramming in vitro and in vivo.
Abstract 11516: Non-Ischemic Fibrosis as a Marker of Adverse Right Ventricular Remodeling - A Multimodality Imaging Study
Authors: Kim Jiwon , Kukar Nina , Ma Claudia L , Medicherla Chaitanya B , Khalique Omar K , Goyal Parag , Venkatesh Prashanth , Devereux Richard B , Horn Evelyn , Weinsaft Jonathan W
Published: July 2021

Background
Non-ischemic mid wall fibrosis (MWF) on cardiac magnetic resonance (CMR) has been linked to poor prognosis in patients with right ventricular (RV) dysfunction, but its link to adverse RV remodeling is unknown.

Methods
The population comprised patients with RV dysfunction (EF<50%) undergoing CMR and transthoracic echo (TTE) within a 14 day (5±3) interval. Cardiac structure, function, and MWF were assessed on CMR; MWF was defined in accordance with standard criteria (mid wall or epicardial septal fibrosis). Pulmonary artery systolic pressure (PASP) was measured on echo. RV wall stress was calculated via an established formula: RV wall stress=(4π*[0.620]
3
*PASP*RVESV)/(3*RV myocardial volume)

Results
118 patients (65% male, 55±18yo) with RV dysfunction were studied, among whom 47% had MWF. Patients with MWF had lower RVEF (34±10 vs. 39±9%; p=0.01) but similar LVEF (40±21 vs 39±18%; p=0.7) and LV volumes (p=NS). RV wall stress was higher with MWF (26±10 vs. 19±9kPa; p<0.001) corresponding to increased RVESV (143±79 vs. 110±36ml; p=0.006), myocardial mass (60±21 vs. 53±17gm; p=0.04), and PASP (52±18 vs. 41±18 mmHg; p=0.001). MWF was associated with increased wall stress among subgroups with isolated RV (p=0.003) and concomitant LV dysfunction (p=0.02). Among RV wall stress components, MWF was independently associated with RV volume (OR=1.17 per 10 ml, [CI 1.04-1.32]; p=0.01) and PASP (OR=1.43 per 10 mmHg, [1.14-1.81]; p=0.002) but not RV mass (OR=0.91 per 10gm, [0.69-1.20]; p=0.5) [model χ
2
=21; p 6-fold more common in the highest, vs. the lowest, common tertile of PASP and RV size (p<0.001; Figure).

Conclusion
MWF strongly relates to increased RV wall stress. Among wall stress components, MWF was independently associated with both RV chamber dilation and afterload, supporting the concept that MWF is a generalized marker of adverse RV chamber remodeling.
Abstract 11545: Moving to a Highly Walkable Neighborhood and Incidence of Hypertension: A Propensity-score Matched Cohort Study
Authors: Chiu Maria , Rezai Mohammad-Reza , Maclagan Laura C , Austin Peter C , Shah Baiju R , Redelmeier Donald A , Tu Jack V
Published: July 2021

Introduction:
Despite growing interest in the built environment and its impact on cardiovascular health, little is known about whether moving to a neighborhood more conducive to walking influences one’s risk of hypertension, a key risk factor of cardiovascular diseases.

Objective:
To conduct the first cohort study examining the association between moving to a highly walkable neighborhood and the risk of incident hypertension among a population-based sample of adults in Ontario, Canada.

Methods:
From the Canadian Community Health Survey (2001-2010), we identified a propensity-score matched cohort of 1057 pairs of Canadian adults who moved from a low (Walk Score<90) walkability neighborhood to either a high (Walk Score≥90) or another low walkability neighborhood. The Walk Score (www.walkscore.com) is a walkability index shown to be valid in multiple geographic locations and at multiple spatial scales. The matched groups were well balanced on 16 important factors, including age, income, marital status and body-mass index. Incident hypertension was ascertained by linking the cohort to administrative health databases using a validated algorithm. Thyroid stimulating hormone testing and annual health examinations were used as the control events.

Results:
We observed a 42% lower risk of incident hypertension among those who moved from a low to high walkability neighborhood vs. those who moved from a low to another low walkability neighborhood (p=0.03) (Figure below). The incidence rate of hypertension was 8.6 per 1,000 person-years among the low to high walkability movers compared to 14.9 per 1,000 person-years among the low to low walkability movers. There were no significant differences in the control event rates between the two mover groups.

Conclusions:
Moving to a highly walkable neighborhood was associated with a significant protective effect on hypertension incidence, suggesting that the built environment can positively influence cardiovascular health.
Abstract 11570: Targeted Disruption of JCAD/KIAA1462, a Coronary Artery Disease-associated Gene Product, Inhibits Angiogenic Processes in Vitro and in Vivo
Authors: Hara Tetsuya , Monguchi Tomoko , Akashi Masaya , Iwamoto Noriko , Mori Kenta , Toh Ryuji , Irino Yasuhiro , Shinohara Masakazu , Furuse Mikio , Ishida Tatsuro , Hirata Ken-ichi
Published: July 2021

Background:
Recent genome-wide association studies newly identified the human KIAA1462 gene as a new locus for coronary artery disease. However, the function of the gene product, named JCAD (junctional protein associated with coronary artery disease), is unknown. Because JCAD is expressed at cell-cell junctions in endothelial cells, we hypothesized and tested whether JCAD regulates angiogenic processes in vitro and in vivo.

Methods and Results:
Cell culture experiments revealed impaired angiogenic ability (WST-1 assay, wound healing, and tube formation) by the knock down of JCAD with siRNA (p<0.05 vs. control siRNA). We generated mice lacking JCAD (JCAD-/-) by gene-targeted deletion of JCAD to address in vivo angiogenic function. JCAD-/- mice did not show differences in development of retinal vasculature. Ex vivo aortic ring model demonstrated impaired neovascularization in aorta from JCAD-/- mice than control wild-type mice (p<0.05). Tumor growth was assessed by monitoring tumor volume after the subcutaneous injection of melanoma cells into the mice. JCAD-/- mice exhibited 45% smaller tumor volume compared with wild-type mice (p<0.001). Histological assessment of tumor exhibited less smooth muscle actin (SMA)-positive neovascularization determined by CD31 staining in tumor of JCAD-/- mice than wild-type mice, indicating that knock-down of JCAD inhibited the vascular maturation in angiogenic process.

Conclusions:
These in vitro and in vivo studies suggest that JCAD has a redundant functional role in physiological angiogenesis, but serves an essential role in pathological angiogenic process.
Abstract 11582: Intercellular Transfer of Mir-126-3p by Endothelial Microparticles Reduces Vascular Smooth Muscle Cell Proliferation and Limits Neointima Formation by Inhibiting Lrp6
Authors: Jansen Feilx , Stumpf Tobias , Nickenig Georg , Werner Nikos
Published: July 2021

Background:
Vascular smooth muscle cell (VSMC) proliferation is of importance in the pathogenesis of vascular diseases such as restenosis or atherosclerosis. Endothelial microparticles (EMP) regulate function and phenotype of target endothelial cells (ECs), but their influence on VSMC biology is unknown.

Hypothesis:
Intercellular communication between ECs and VSMCs via EMPs regulates vascular remodelling.

Methods and results:
Systemic treatment of mice with EMPs after vascular injury reduced neointima formation in vivo. In vitro, EMP uptake in VSMCs diminished VSMC proliferation and migration, both pivotal steps in neointima formation. To explore the underlying mechanisms, Taqman microRNA-array was performed and microRNA (miR)-126-3p was identified as the predominantly expressed miR in EMP. Confocal microscopy revealed an EMP-mediated miR-126 transfer into recipient VSMCs. Expression of miR-126 target protein LRP6, regulating VSMC proliferation, was reduced in VSMCs after EMP treatment. Importantly, genetic regulation of miR-126 in EMPs showed a miR-126-dependent inhibition of LRP6 expression, VSMC proliferation and neointima formation in vitro and in vivo, suggesting a crucial role of miR-126 in EMP-mediated neointima formation reduction. Exposure of endothelial cells to pathological hyperglycaemic conditions prior to EMP release abrogated EMP-promoted neointima formation reduction. Finally, analysis of miR-126 expression in circulating MPs in 176 patients with coronary artery disease revealed a reduced PCI rate in patients with high miR-126 expression level, supporting a central role for MP-incorporated miR-126 in vascular remodelling.

Conclusions:
EMPs reduce VSMC proliferation, migration and subsequent neointima formation by delivering functional miR-126 into recipient VSMCs.
Abstract 11583: Length of Hospital Stay and All-Cause Mortality Among Adults With Atrial Fibrillation Hospitalized for Bleeding During Treatment With Warfarin, Dabigatran, or Rivaroxaban
Authors: Charlton Blake , Adeboyeje Gboyega , Barron John J , Grady Deborah , Shin Jaekyu , Redberg Rita
Published: July 2021

Introduction:
Little is known about the relative outcomes of bleeding complications during warfarin therapy compared to bleeding complications during treatment with dabigatran or rivaroxaban.

Hypothesis:
Because warfarin is more easily reversible, bleeding complications during warfarin therapy may be associated with better outcomes.

Methods:
We performed a retrospective cohort study using a US commercial claims database of 38 million members from 11/1/10 to 3/31/14. Participants were adults with atrial fibrillation hospitalized for bleeding after starting warfarin, dabigatran, or rivaroxaban. The outcomes were length of hospital stay, ICU admission, length of ICU stay, and all-cause mortality. The analyses used propensity scores as covariates in a multivariable Poisson regression. Subgroup analyses examined patients with chronic kidney disease, heart failure, more than 7 comorbidities, hemorrhagic stroke, major gastrointestinal bleed, those over 75, those without ICU admission, and those restarting anticoagulation after discharge.

Results:
Admissions for bleeding included 2446 warfarin, 442 dabigatran, and 256 rivaroxaban users. Warfarin users were older than dabigatran or rivaroxaban users (74 vs 69 vs 68 years) and had more comorbidities. After adjustment, warfarin was associated with a 2.2 mean day increase in hospital stay (CI 2.0 - 2.5) compared to dabigatran and a 3.1 mean day increase (CI 2.8 - 3.4) compared to rivaroxaban. There were no significant differences in the proportions of ICU admissions among the 3 groups. Warfarin was associated with a mean ICU stay increase of 2.3 days (CI 0.94 - 3.6) compared to dabigatran. After 3.4 years follow up, there was a 17% adjusted mortality in the warfarin cohort, 13% in the dabigatran cohort, and 6% in the rivaroxaban cohort. Warfarin was associated with longer hospitalization in every subgroup.

Conclusions:
Despite warfarin’s reversibility, bleeding complications during warfarin therapy are associated with longer hospitalization and higher adjusted mortality. However, because patients treated with newer oral anticoagulants are younger and healthier, randomized trials are necessary to better understand these unexpected differences in bleeding-related outcomes.
Abstract 11594: Reduction in Subtypes and Sizes of Myocardial Infarction With Ticagrelor in PEGASUS-TIMI 54
Authors: Bonaca Marc P , Wiviott Stephen D , Morrow David A , Steg P. Gabriel , Hamm Christian , Bhatt Deepak L , Storey Robert F , Kuder Julia , Murphy Sabina A , Magnani Giulia , Budaj Andrej , Theroux Pierre , Nicolau José C , Parkhomenko Alexander , López-Sendón José , Dellborg Mikael , Diaz Rafael , Van de Werf Frans , Corbalán Ramón , Jensen Eva C , Braunwald Eugene , Sabatine Marc S
Published: July 2021

Objective:
Ticagrelor reduced the risk of CV death, MI or stroke (MACE) in stable patients with prior MI in PEGASUS-TIMI 54. We investigated the efficacy of ticagrelor in reducing different subtypes and sizes of MI.

Methods:
MIs were adjudicated by the blinded TIMI Clinical Events Committee with definitions consistent with the Third Universal Definition of MI. Each MI was categorized by subtype and fold elevation of peak troponin (Tn) over the upper limit of normal (ULN). Results for both doses of ticagrelor were pooled in comparison to placebo.

Results:
A total of 1042 MIs occurred in the 21,162 randomized patients over a median follow up of 33 months. The majority (76%) of the MIs were spontaneous (Type 1), with demand MI (Type 2) and PCI-related (Type 4) accounting for 13% and 10% respectively (Figure Left); sudden death MI (Type 3) and CABG-related MI (Type 5) each accounted for <1%. Using fold elevation in Tn, half of MIs (520, 50%) had a peak Tn ≥10x ULN and 21% of MIs (220) had a peak Tn ≥100x ULN (Figure Right). A total of 21% (224) were STEMI. Overall ticagrelor reduced MI at 3 yrs (4.47% vs 5.25%, HR 0.83, 95% CI 0.72 - 0.95, p=0.0055). The benefit was highly consistent among the different subtypes of MI (Figure left) and with increasing size of MI by fold elevation of Tn (Figure right) and for STEMI (HR 0.60, 95% CI 0.46 - 0.78, p=0.0002).

Conclusion:
In stable outpatients with a history of MI the majority of recurrent MI events are spontaneous and associated with a high biomarker elevation. Ticagrelor significantly reduces the incidence of MI consistently among different subtypes and biomarker sizes, with the greatest absolute reduction in spontaneous MIs, large MIs, and STEMI.
Abstract 11751: Beneficial Impact of Dipeptidyl-peptidase-4 inhibitors on Mortality of Patients With Hospitalized Heart Failure Patients With Diabetes Mellitus
Authors: Sato Akihiko , Yoshihisa Akiomi , Kanno Yuki , Takiguchi Mai , Miura Shunsuke , Shimizu Takeshi , Nakamura Yuichi , Yamauchi Hiroyuki , Owada Takashi , Abe Satoshi , Suzuki Satoshi , Oikawa Masayoshi , Sakamoto Nobuo , Yamaki Takayoshi , Sugimoto Koichi , Kunii Hiroyuki , Nakazato Kazuhiko , Suzuki Hitoshi , Saitoh Shu-ichi , Takeishi Yasuchika
Published: July 2021

Background:
Heart failure (HF) and diabetes mellitus (DM) often co-exist. Treatment of DM in patients with HF is challenging since some therapies for DM are contraindicated in HF. Although previous experimental studies have reported that DPP-4 inhibitors improve cardiovascular function, it still remains unclear whether DPP-4 inhibition improves mortality of HF patients with DM. Therefore, we examined impacts of the DPP-4 inhibition on mortality in hospitalized HF patients using propensity score matching.

Methods and Results:
We performed prospective observational study regarding to hospitalized HF. Out of 1011 original HF patients cohort, 112 patients were treated with DPP-4 inhibitors. Propensity score for treatment with DPP-4 inhibitors were estimated for each patient by logistic regression with clinically relevant baseline variables including age, estimated GFR, HbA1c, usages of α-glucosidase inhibitor, sulphonylurea, biguanide and insulin. The propensity matched cohort 1:1 was assessed based on propensity scores (DPP-4 inhibitors, n = 82 and non-DPP-4 inhibitors, n = 82). Kaplan-Meier analysis demonstrated that cardiac and all-cause mortality was significantly lower in the DPP-4 inhibitor group than in the non-DPP-4 inhibitor group (cardiac mortality: 7.3% vs. 23.2%, P=0.006; all-cause mortality: 17.1% vs. 42.7%, P=0.002, by a log-rank test) in the propensity matched cohort. In the multivariable Cox proportional hazard analyses, after adjusting for other potential confounding factors, the use of DPP-4 inhibitors was an independent predictor of cardiac and all-cause mortality (cardiac mortality: HR 0.322, 95% CI 0.127-0.819, P = 0.017; all-cause mortality: HR 0.517, 95% CI 0.273-0.978, P = 0.042) in HF patients with DM.

Conclusions:
Our data suggest that DPP-4 inhibitors may improve cardiac and all-cause mortality in patients with HF and DM.