bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10404: The Role of Patient, Community and Healthcare System Factors in the Variability of Heart Failure Hospital Readmissions
Authors: Saef Joshua , Kochar Arshneel S , Martyn Michael T , Montgomery Robert A , Cremer Paul , Kim Yuli Y , Menon Venu , Tang Wai Hong
Published: March 2022

Introduction:
The Hospital Readmissions Reduction Program (HRRP) penalizes hospitals by reducing Medicare (CMS) reimbursement for those institutions with higher rates of readmissions following hospitalizations for heart failure (HF). Understanding the contributors to readmission following HF hospitalization can identify meaningful areas for intervention. We examine whether community and patient or healthcare system factors contribute more to variability in HF readmissions.

Methods:
We compiled CMS hospital data on HF readmissions, CMS physician reimbursement data, and 2020-21 County Health Rankings (Credit: University of Wisconsin). The outcome was the ratio of a hospital’s HF readmissions to HF discharges. Physician/healthcare system factors included total number of cardiac subspecialists, presence of all subspecialties, and the mean proportion of reimbursed charges. Patient/community factors included mean Hierarchical Condition Category (HCC) risk score (quantifies expected healthcare costs for CMS beneficiaries based on ICD-10 coding), median household income, the proportion of residents reporting no physical activity, and access to food stores. Models were created using linear regression. Model of best fit was determined using R
2
, AIC, BIC in model training data and mean absolute prediction error (MAPE) and root mean square prediction error (RMSE) in test data.

Results:
The linear regression model incorporating community and patient factors explained greater variability in HF readmission rates and performed with greater accuracy in the test data (R
2
0.177; AIC -6879.1; BIC -6840.542; MAPE 0.030; RMSE 0.039) than the model incorporating physician/healthcare system factors (R
2
0.021; AIC -6566.7; BIC -6539.191; MAPE 0.032; RMSE 0.041). HCC score and level of physical activity were associated with the greatest effect sizes on the outcome.

Conclusions:
At a county level, community/patient factors appear to contribute more to variability in hospitals’ HF readmission rates than physician/healthcare system factors. Further analyses should explore other community, patient, and provider factors that contribute. The HRRP does not account for community or patient factors, indicating its limitations.
Abstract 10410: Human Stem Cell-Derived Endothelial Cells Suppress Automaticity of Stem Cell-Derived Cardiomyocytes
Authors: Garbern Jessica C , Li Qiang , Liu Ren , Mancheno Juncosa Estela , Lin Zuwan , Elwell Hannah L , Aoyama Junya , Morgan Sokol K , Liu Jia , Lee Richard T
Published: March 2022

Clinical translation of stem cell therapies for heart disease is limited by a risk of potentially life-threatening ventricular arrhythmias seen following cardiomyocyte delivery in large animal models. Enhancing cardiomyocyte maturation may reduce this arrhythmogenic risk by reducing automaticity of delivered cardiomyocytes. We tested whether human induced pluripotent stem cell (hiPSC)-derived endothelial cells can enhance maturation and suppress automaticity of iPSC-derived cardiomyocytes in vitro. We found that co-culture of hiPSC-derived endothelial cells with hiPSC-derived cardiomyocytes significantly increased protein expression of cardiac troponin T, cardiac troponin I, Kir2.1, connexin 43, and CD36. In addition, using a stretchable mesh nanoelectronics device, we found that hiPSC-derived endothelial cells accelerated electrical maturation of hiPSC-derived cardiomyocytes and progressively suppressed cardiomyocyte automaticity in vitro (Figure). Using single cell RNA-seq, we identified a subpopulation of hiPSC-derived cardiomyocytes that is eliminated upon co-culture with hiPSC-derived endothelial cells. Further work will investigate whether this subpopulation of cardiomyocytes is responsible for automaticity of cardiomyocyte cultures.

Figure.
Induced pluripotent stem cell (iPSC)-derived cardiomyocytes alone (CM only) or iPSC-derived cardiomyocytes co-cultured with iPSC-derived endothelial cells (CM+EC) were seeded onto a stretchable mesh nanoelectronics device. Unstimulated voltage tracings at day 30 of cardiomyocyte differentiation show cardiomyocytes with a slower beating rate and more narrow action potential when co-cultured with iPSC-derived endothelial cells compared to iPSC-derived cardiomyocytes alone.
Abstract 10411: Recurrent Spontaneous Coronary Artery Dissection
Authors: Echeverry Tatiana , Mehan Shivalika , Williams Karlene
Published: March 2022

Spontaneous coronary dissection (SCAD) accounts for 25% of ACS in females <50 years of age. The recurrence rate of SCAD within one to two years is 11%. Currently, there are no universal guidelines for the treatment of SCAD. However, the literature reports higher rates of complications associated with stenting than with medical treatment. Beta-blockers are believed to be protective against SCAD recurrence due to its direct mechanism of action on the vasculature and heart. The following case describes a patient on recommended medical therapy, including a beta-blocker who presented with a dissection of the second diagonal branch.

A 51-year-old female with a history of SCAD in 2007 and right MCA aneurysm on metoprolol, presented with sudden onset of mid-sternal chest pain radiating to the back. The initial EKG showed T wave inversions in lead V2-V3 and elevated troponin of 2.58 which peaked at 9.9. The patient immediately underwent cardiac catheterization which revealed spontaneous dissection in the circumflex marginal. An ECHO revealed EF of 60-65% without wall motion abnormalities. The patient was treated medically with DAPT, and continuation of her home medication metoprolol.

SCAD is a rare etiology of ACS with a predilection for young to middle-aged females. In the United States, SCAD has an approximate yearly incidence of 3.4% in females. The coronary vessels affected more frequently are the LAD and the RAC with 57% and 29% rate of dissection respectively. SCAD was noted to have a recurrence rate of 11% within 2-3 years with an increased recurrence rate of 29% at the 10-year follow-up. While the reasons for recurrence are unclear, there is a clear association between vessel tortuosity and HTN with higher rates of recurrence. A previous study reported that beta-blockers can reduce the risk of recurrence by almost two-thirds. The decreased risk was attributed to the mechanism of action of beta-blockers: decreasing intracoronary shear stress, decreasing heart contractility, and reducing aneurysm degeneration. Our patient suffered a recurrent case of SCAD despite recommended treatment with a beta-blocker. Further research is needed to risk-stratify patients and to clarify if a specific dose or type of beta-blocker will protect against SCAD recurrence.
Abstract 10415: Dysregulation of FOXO-FOXM1 Signaling Inhibits Maturation of IPSC-Derived Cardiomyocytes in 3D Suspension Culture
Authors: Garbern Jessica C , Elwell Hannah L , Mancheno Juncosa Estela , van den Berg Daphne , Sokol Morgan K , Lee Richard T
Published: March 2022

Directed differentiation of human pluripotent stem cells (PSC) into cardiomyocytes via manipulation of Wnt signaling leads to generation of immature cardiomyocytes, more closely resembling a fetal state. It has become increasingly apparent that metabolic parameters regulate of cardiomyocyte maturation. The forkhead box (FOX) family of transcription factors has previously been shown to regulate metabolic phenotype in neonatal cardiomyocytes through a balance between FOXO and FOXM proteins. Therefore, we hypothesized that dysregulation of FOXO-FOXM1 signaling inhibits maturation of iPSC-derived cardiomyocytes (iPSC-CMs). We cultured iPSC-CMs in 3D suspension culture using an orbital shaker. iPSC-CMs were treated with RCM-1 (FOXM1 inhibitor), LOM612 (FOXO nuclear translocator), or AS1842856 (FOXO inhibitor) starting 2 days after onset of beating. We found that inhibition of FOXO with AS1842856 resulted in loss of expression of cardiac-specific markers such as cardiac troponin T as well as loss of spontaneous beating. In contrast, inhibition of FOXM1 with RCM-1 or activation of FOXO with LOM612 resulted in retention of a cardiomyocyte phenotype with continued expression of cardiac troponin T but with significantly increased expression membrane protein expression of Kir2.1 (Figure), the protein largely responsible for maintaining the resting membrane potential in cardiomyocytes. These results suggest that inhibition of FOXM1 and/or activation of FOXO signaling may facilitate maturation of iPSC-derived cardiomyocytes.

Figure.
(A) % of TNNT2+ iPSC-derived cardiomyocytes that express Kir2.1 and (B) Mean fluorescence intensity of Kir2.1 in iPSC-derived cardiomyocytes after treatment with DMSO (vehicle control), RCM-1, LOM612, or AS1842856. *p<0.05, ***p<0.001, ****p<0.0001 by one-way ANOVA with Dunnett’s multiple comparisons test.
Abstract 10424: Spatial Ventricular Gradient Changes Predict Acute Pulmonary Embolism Severity
Authors: Marcus Mason , Stabenau Hans , Manning Warren J , Carroll Brett , Waks Jonathan W
Published: March 2022

Introduction:
The severity of an acute pulmonary embolism (PE) can be assessed using hemodynamics, right ventricular (RV) strain on imaging, and cardiac biomarkers. The spatial ventricular gradient (SVG) is a vectorcardiographic measurement acquired from a 12-lead ECG that reflects cardiac loading conditions via electromechanical coupling and could aid in risk stratification in acute PE.

Hypothesis:
SVG is correlated with RV strain, and predicts adverse events in patients with acute PE.

Methods:
Retrospective cohort study of patients with acute PE. ECG signs of RV strain (S1Q3T3, precordial T-wave inversions, RBBB); imaging (CT and TTE RV/LV ratios); and outcome data (30-day mortality, need for vasopressor or advanced therapy) were obtained. The SVG vector was regressed on degree of RV dysfunction. Odds of adverse outcome after PE were regressed on the SVG and covariates (imaging data, age, gender, ECG signs) using a logit model.

Results:
ECGs from 318 patients (48% male, age 62.2 ± 16.4 y) with acute PE were analyzed; 44 adverse events (13. 8%) were reported. Worse RV hypokinesis and decreasing tricuspid annular plane systolic excursion (TAPSE) were both associated with less positive X and Y, and a more positive SVG Z vector components (p<0.001 for all). The Figure shows receiver operating characteristic (ROC) curves of models using conventional ECG, imaging, and SVG data. Compared to conventional ECG markers and imaging, the addition of SVG to imaging improved the area under the ROC curve from 0.62 vs 0.72 (p=0.013).

Conclusion:
The SVG vector is correlated with right heart dysfunction in acute PE. The SVG vector has a better prognostic value than traditional ECG markers, and may improve risk stratification in acute PE.
Abstract 10429: Atrial Pitx2c Overexpression Increased Atrial Arrhythmias with Altered Calcium Handling
Authors: Baba Shunsuke , Akaike Toru , Bochimoto Hiroki , Shinjo Satoko , Minamisawa Susumu
Published: March 2022

Introduction:
We have previously reported that the atrial cardiomyocyte-specific
Pitx2c
overexpression impaired sinus node function. It is well known that sinus node dysfunction is associated with atrial fibrillation (AF) and
PITX2C
increases in patients with chronic AF. Although
Pitx2c
overexpression in the atrium may be susceptible to atrial arrhythmias, the mechanism is not well understood.

Hypothesis:
Pitx2c
overexpression in the atrium induces atrial arrhythmias with altered calcium handling.

Methods:
We generated the atrial cardiomyocyte-specific
Pitx2c
overexpression mice by crossing two types of mice. Then, we examined AF inducibilities, the expressions of genes related to left-right axis determination and AF, and monophasic action potential durations of B6-Tg (
CAG-LSL-Pitx2c
);

SLN
Cre/+

(overexpression: OE) and B6 (wild type: WT) mice.

Results, Conclusions:
Pitx2c
was up-regulated in the right atrium (RA) of OE than WT mice. AF increased significantly following burst pacing in OE (52%, n=6) than WT (7%, n=9) mice. Furthermore, episodes of atrial arrhythmias such as premature atrial conduction and AF were increased in OE mice.
TBX3
,
Shox2
and
Scn5a
were down-regulated, and
Kcne1
was up-regulated significantly in the atrium of OE than WT mice (n=8, each group). Especially in the RA of OE mice,
Cacna1c
and
Serca2
, which were calcium regulatory genes, were significantly down-regulated. In addition, we found that monophasic action potential duration was shorter in RA of the OE mice than WT mice. In conclusion, cardiomyocyte-specific
Pitx2c
overexpression in RA induces atrial arrhythmias with altered calcium handling. The transcription factor
Pitx2c
promotes electrical remodeling similar to clinical data.
Abstract 10431: Impact of Cardiac Rehabilitation on Reducing Cardiovascular Events and Subsequent Medical Expenses for One Year in Patients with Transcatheter Aortic Valve Implantation
Authors: Yokota Yuya , Koba Shinji , Tsunoda Fumiyoshi , Shoji Makoto , Shinke Toshiro
Published: March 2022

Introduction:
It remains unclear whether cardiac rehabilitation (CR) can reduce medical expenses (ME)in patients with Transcatheter Aortic Valve Implantation (TAVI).

Hypothesis:
Outpatients CR reduced the cardiovascular events (CEs) and the total ME for one year in patients after TAVI.

Methods:
This retrospective analysis enrolled consecutive 148 patients who admitted TAVI treatment at the Showa University Hospital, between December 2015 and September 2019. Exclusion criteria was in-hospital death, difficulty walking at discharge and patients who could not be followed up after the hospital discharge. The subsequent ME for outpatient clinic and/or rehospitalization due to CEs in avarage 1.5 years after the discharge were compared between the CR group and non-CR group. CEs were defined as death, ACS, angina, stroke, and heart failure.

Results:
The CR group was significantly reduced the CEs compared with the non-CR group (logrank = 4.538 p = 0.033). (figure1)The CR group was significantly increased the outpatient ME (p < 0.001). However, rehospitalization and total ME were significantly lower in the CR group (p = 0.003, p = 0.002). (figure2)

Conclusions:
Outpatients CR reduced the CEs and the total ME for one year in patients after TAVI.
Abstract 10434: Gaps in Ldl-C Control According to Cardiovascular Risk Status and Statin Use in Us Adults
Authors: Yang Yueh-Ning , FAN WENJUN , Wong Nathan D
Published: March 2022

Background:
Current US guidelines since 2013 have recommended statin use for high cardiovascular (CV) risk adults including those with atherosclerotic cardiovascular disease (ASCVD), regardless of LDL-C levels. Recent data among US population-representative adults regarding extent of LDL-C control in high CV risk persons are lacking.

Methods:
We examined among 4,484 US adults (representing 231 million) from the National Health and Nutrition Examination Surveys 2015-2018 the extent of statin use and remaining high LDL-C levels according to risk group as defined by the pooled cohort equation (PCE): low (<5%), intermediate (5-
<
20%), high risk without ASCVD (>20% 10-year risk), diabetes without ASCVD, and high and very high risk ASCVD as defined by the 2018 cholesterol management guideline based on multiple major ASCVD events or high risk conditions.

Results:
Overall, 18.9% (representing 43.7 million) of US adults were on statin therapy in our cohort; this varied across risk groups from 1.4% (low risk), 10.7% (intermediate risk), 26.2% (high risk without ASCVD), 48.8% (diabetes without ASCVD), 50.8% (ASCVD high risk) and 75.4% (ASCVD very high risk), with additional ezetimibe use <5% in all groups. The figure below shows, despite statin therapy (with or without ezetimibe), >45% of high-risk primary prevention persons still have LDL-C
>
100 mg/dL, >70% of those with DM to have LDL-C
>
70 mg/dL, and >60% of high risk and >70% of very high-risk adults with ASCVD to have LDL-C
>
70 mg/dL.

Conclusions:
Despite statin-focused guidelines since 2013, many US adults recommended for statin therapy are not on statins, and of those on statins, many have suboptimal LDL-C levels, warranting further LDL-C lowering with higher intensity statins and/or non-statin agents.
Abstract 10437: “Explainable Artificial Intelligence (ai) in Cardiology”: A Tool to Provide Personalized Predictions on Cardiac Health States Among Older Adults Engaged in Physical Activity
Authors: Loh De Rong , Yeo Si Yong , Tan Ru San , Gao Fei , Koh Angela S
Published: March 2022

Introduction:
As a prevention strategy, the effect of physical activity on older adults is likely heterogeneous against a background of individual ageing trajectories. While machine learning models that combine various systemic signals may aid in predictive modeling, the inability to rationalize predictions at a patient personalized level is a major shortcoming in AI.

Methods:
We applied a novel approach using Shapley Additive Explanations (SHAP) methodology on a dataset of older adults whose physical activity levels were studied in conjunction with changes in left ventricular (LV) structure. The SHAP approach provided intelligible visualization on the magnitude of the impact of the features in their physical activity levels on their LV structure.

Results:
As proof of concept, we studied n = 86 older adults (mean age 72±4 years). Using repeated K-cross validation on the train set (n = 68), we found the Random Forest Regressor with the most optimal hyperparameters, which achieved the lowest mean squared error. With the trained model, we evaluated its performance by reporting its mean absolute error and plotting the correlation on the test set (n = 18) (Fig 1). A collective force plot for individually numbered patients (horizontal axis) showing magnitude (i.e., effect) of physical parameters (higher in red; lower in blue) towards prediction of LV structure (Fig 2). For example, for patient number 6, basal metabolic rate was the predominant positive factor on LV structure, outweighing other weaker positive factors and negative factor contributed by body fat mass (Figure 3). In contrast, LV structure in patient number 11 was predicted jointly by several weaker positive factors without any single predominant factor (Figure 4).

Conclusions:
As a tool that identified specific features in physical activity that predicted cardiac structure on a per patient level, our findings support a role for explainable AI to be incorporated into personalized cardiology strategies.
Abstract 10442: Temporal Changes in Plasma Lipidome in Patients with St-Segment Elevation Myocardial Infarction: Impact of Reperfusion
Authors: Surendran Arun , Atefi Negar , Ismail Umar , Shah Ashish , Ravandi Amir
Published: March 2022

Aim:
We aim to investigate the temporal changes in plasma lipidome before and after reperfusion in ST-segment elevation myocardial infarction (STEMI) patients and their association with myocardial injury.

Methods:
Venous blood samples were drawn from STEMI patients (N=80) serially before percutaneous coronary intervention (PCI) and at 2 h, 24 h, 48 h, and 30 days after PCI. Plasma lipid profiling (322 lipids) was performed on STEMI patients and age and gender-matched control subjects (N=50) using an LC/MS platform.

Results:
Overall, 56.01% of the identified lipid species were significantly altered (corrected
p<0.05
) in the first 24 h following reperfusion in STEMI patients. During early reperfusion, except oxidized phospholipids, the majority of lipid classes/subclasses (14 out of 25) were significantly lower (corrected
p<0.05
) at 2 h post-reperfusion compared to the ischemic state. Of all the lipid classes/subclasses, fatty acids showed the most remarkable change (74.5% lower) in the first 24 h after reperfusion. Multivariable linear regression analyses following adjustment of traditional risk factors identified 33 lipid species that significantly associate (p<0.05) with change in troponin concentration (delta troponin) at different time intervals. Five of these lipid species, namely, acylcarnitine 18:2, TG 51:0, PE (O-38:5), LPC 17:1, and LPC 18:0, could stratify patients in the highest tertile of delta troponin from those in the lowest tertiles. These lipids also were correlated with in-hospital cardiovascular events. Acylcarnitine 18:2, LPC 17:1, and LPC 18:0 as well as their respective whole class amount, were significantly higher (p<0.05) in the STEMI population than the control subjects.

Conclusions:
Our analyses elucidated a detailed characterization of the temporal alterations in plasma lipidome that occur during human myocardial reperfusion injury.
Abstract 10444: New Predictors and Long-Term Outcomes in ST-Elevation Myocardial Infarction with Cardiac Rupture After Primary Percutaneous Coronary Intervention
Authors: Kawamata Hirofumi , Yanishi Kenji , Shoji Keisuke , Hori Yusuke , Fujioka Ayumu , Teramukai Satoshi , Nakamura Takeshi , Matoba Satoaki
Published: March 2022

Introduction:
Cardiac rupture (CR) is a serious complication of acute myocardial infarction. Primary percutaneous coronary intervention (pPCI) reduces the incidence of CR. However, the risk factors and long-term outcomes in patients with CR after pPCI remain unclear.

Aims:
To investigate the clinical predictors and outcomes of CR after pPCI.

Methods:
This was a retrospective, case-control, multi-center study. A total of 2,444 consecutive patients with ST-elevation myocardial infarction (STEMI) undergoing pPCI from 2009 to 2015 were included; 33 patients had CR (1.4%): 19 were assigned as early-CR (≤72 h) and 14 as late-CR (>72 h). The 132 controls (non-CR) were randomly selected by matching the 2,411 STEMI patients without CR at a 1:4 ratio.

Results:
Figure.1 showed that female, acute hyperglycemia, thrombocytopenia (platelet<15х10
4
/μL), and incomplete revascularization (post-PCI thrombolysis in myocardial infarction [TIMI]<3) were independent risk factors for CR (P<0.05). Univariate logistic regression after adjusting age and sex showed that acute hyperglycemia and post-PCI TIMI<3 were significantly associated with early-CR, whereas thrombocytopenia was strongly associated with late-CR. In-hospital mortality rate was significantly higher in the CR than the non-CR group (66.7% vs 6.8%, P<0.0001). Emergency surgical repair exhibited a strong association with in-hospital death. Kaplan-Meier survival curve in Figure.2 showed no significant difference between surviving STEMI patients with CR and non-CR (Log-rank P=0.26).

Conclusions:
Acute hyperglycaemia and thrombocytopenia are new predict factors for early- and late-CR, respectively. The clinical risk factors of early- and late-CR in pPCI era may differ. Emergency surgical repair affects with in-hospital mortality, and surviving CR patients have a similar post-discharge survival rate compared with surviving non-CR patients.
Abstract 10450: Higher Body Mass Index is Associated with a Higher Prevalence of Thin-Cap Fibroatheroma in Younger Patients with Type 2 Diabetes Mellitus
Authors: Katamine Masahiro , Minami Yoshiyasu , Asakura Kiyoshi , Katsura Aritomo , Kinoshita Daisuke , Hashimoto Takuya , KAMEDA RYO , Meguro Kentaro , Shimohama Takao , Ako Junya
Published: March 2022

Introduction:
High body mass index (BMI) is associated with increased incidence of type 2 diabetes (T2D) and subsequent cardiovascular disease (CVD). However, the association between the BMI and the characteristics of coronary plaque in younger T2D patients with CVD remains to be elucidated.

Hypothesis:
Higher BMI is associated with a higher prevalence of vulnerable coronary plaque in younger T2D patients with CVD.

Methods:
A total of 140 consecutive younger (<65 years) T2D patients with CVD, who underwent optical coherence tomography (OCT) imaging of the culprit lesion were included. The patients were classified into either the higher BMI group (BMI ≥25.8 kg/m
2
, n=70) or the lower BMI group (BMI <25.8 kg/m
2
, n=70) according to the median of BMI. The characteristics of culprit plaque assessed by OCT were compared between the two groups.

Results:
The prevalence of thin-cap fibroatheroma (TCFA) (34.8 vs. 17.4%,
p
=0.020) and lipid-rich plaque (44.9 vs. 26.1%,
p
=0.021) was significantly higher in the higher BMI group than in the lower BMI group (Panel A). The prevalence of TCFA was further compared according to the tertile of LDL-C levels. A significant trend toward higher prevalence of TCFA according to the increase in LDL-C levels was observed in patients with higher BMI (
p
=0.017) (Panel B), although the trend was not significant in patients with lower BMI (
p
=0.487) (Panel C).

Conclusions:
Higher BMI was associated with a higher prevalence of TCFA in younger T2D patients with CVD. Higher LDL-C level was associated with a higher prevalence of TCFA among patients with higher BMI although the association was not significant among patients with lower BMI.
Abstract 10451: A Potential Therapeutic Antibody to Induce Collateral Formation in Cardiovascular Diseases
Authors: Amartey Jason , Wahid Mussarat , Bhalla Sohni R , Bates David O
Published: March 2022

Introduction:
Lack of efficient collateralisation during vascular occlusion leads to tissue ischemia in coronary, peripheral and cerebrovascular disease. Patients with peripheral, coronary, and cerebrovascular disease have elevated levels of the anti-angiogenic isoform of VEGF (VEGF-A
165
b), which correlate with poorer outcomes. In experimental animals, VEGF-A
165
b neutralisation improves blood flow and collateralisation after femoral or coronary artery ligation.

Hypothesis:
We tested the hypothesis that a potent, high affinity, humanised neutralising antibody to VEGF-A
165
b could have therapeutic potential in models of cardiovascular disease.

Methods:
A mouse monoclonal antibody to VEGF-A
165
b was humanised by cloning and site directed mutagenesis. Multiple clones were screened, and one with high affinity (measured by biolayer interferometry) was amplified. The efficacy in vitro was tested using endothelial cell migration assays and in vivo using the hindlimb ischemia (HLI) model in C57Bl6 mice fed a high fat high sucrose (HFHS) diet, and in Zucker Diabetic Fatty rats.

Results:
One clone (HC4LC2) had a VEGF-A
165
b affinity of 600pM. 0.3μg/ml of this clone reversed the inhibitory effect of recombinant human VEGF-A
165
b (31±4%, N=6 of VEGF-A
165
a alone) on migration of endothelial cells to 40ng/ml rhVEGF-A
165
a (89±9% N=3). Human monocyte dependent inhibition of VEGF-A
165
a mediated migration was dose dependently reversed by HC4LC2 (EC50, 55ng/ml, N=9 per concentration). HLI in HFHS mice impaired blood flow after 28 days in IgG treated mice (70±7.7% of pre-ischemic blood flow, N=6), which was restored to normal (93.3±5.5, p<0.05, N=8) by intraperitoneal injection of 1mg/kg HC4LC2. Blood flow recovery after HLI was also seen in ZDF rats treated with HC4LC2 (106±16% of pre-ischemic flow, N=5) compared with IgG treated animals (76±.9%, N=5, p<0.05, two-way ANOVA, all values mean ±SEM).

Conclusions:
These results indicate that HC4LC2 is a humanised, high affinity neutralising antibody to VEGF-A
165
b that could have therapeutic potential for patients with cardiovascular disease, by enhancing collateral formation.
Abstract 10455: HFA-PEFF Score: A Prognostic Value in Heart Failure with Preserved Left Ventricular Ejection Fraction Patients
Authors: Egashira Koichi , Tsujita Kenichi , Yamamoto Eiichiro , Sueta Daisuke
Published: March 2022

Introduction:
The HFA-PEFF score is recognized as a simple method to diagnose heart failure (HF) with preserved left ventricular ejection fraction (HFpEF). This study aimed to evaluate the relationship between the score and cardiovascular outcomes in HFpEF patients.

Methods:
505 consecutive HFpEF patients were prospectively observed for up to 1,500 days or until the occurrence of cardiovascular events. Cardiovascular outcomes were compared between the HFA-PEFF score 0-4 group (low-intermediate score group) and the HFA-PEFF score 5-6 group (high score group). Overall, 237 cardiovascular events were observed during the follow-up period (median: 1,154 days).

Results:
Kaplan-Meier analysis showed that there was no significant difference about composite cardiovascular events between low-intermediate score group and high score group (P=0.251), whereas the high score group was at higher risk of HF-related events than the low-intermediate score group (P<0.001). Multivariable Cox proportional hazards analysis with the significant factors from the univariate analysis showed that the HFA-PEFF score (hazard ratio: 1.20, 95% confidence interval: 1.01-1.42, P=0.036) significantly predicted future HF-related events. Receiver operating characteristic analysis showed that the HFA-PEFF score significantly predicted HF-related events (area under the curve, 0.634; 95% CI, 0.575-0.693; P<0.001). The cutoff HFA-PEFF score was 4.5 for the identification of HF-related events. Decision curve analysis revealed that combining HFA-PEFF score with conventional prognostic factors ameliorated risk-prediction of HF-related events.

Conclusions:
HFA-PEFF score may be useful for predicting HF-related events in HFpEF patients.
Abstract 10456: Direct Oral Anticoagulant is Associated with a Lower Prevalence of Thin-Cap Fibroatheroma in Patients with Coronary Artery Disease
Authors: Kinoshita Daisuke , Minami Yoshiyasu , Kakizaki Ryota , Ishida Kohki , Fujiyoshi Kazuhiro , Sato Toshimitsu , Kato Ayami , Nagata Takako , Asakura Kiyoshi , Katamine Masahiro , Katsura Aritomo , Ako Junya
Published: March 2022

Introduction:
The reduced incidence of cardiovascular events in patients with direct oral anticoagulant (DOAC) has been demonstrated. However, the association between taking DOAC and the characteristic of coronary plaque remains to be elucidated.

Hypothesis:
Taking DOAC is associated with a lower prevalence of vulnerable plaque in patients with coronary artery disease (CAD).

Methods:
A total of 2168 coronary plaques in consecutive 1439 patients who underwent optical coherence tomography imaging of the culprit or non-culprit lesion were analyzed. The prevalence of thin-cap fibroatheroma (TCFA) were compared between patients with DOAC (149 plaques in 105 patients) and those without (2019 plaques in 1334 patients).

Results:
The prevalence of TCFA was significantly lower in patients with DOAC than those without in both culprit lesion (27.3% vs. 15.4%, p=0.002) and non-culprit lesion (22.1% vs. 5.2%, p<0.001) (Panel A). In addition to P2Y12 inhibitor intake (odds ratio: 0.941 [95% confidence interval: 0.890-0.995], p=0.034), taking DOAC was independently associated with a lower prevalence of TCFA at any lesion (odds ratio: 0.891 [95% confidence interval: 0.837-0.949], p<0.001) after adjustment of confounders. The prevalence of TCFA at any lesion was significantly lower in patients with a combination of DOAC and P2Y12 inhibitor than those on either DOAC or P2Y12 inhibitor and those without (Panel B).

Conclusions:
Taking DOAC was associated with a lower prevalence of TCFA in patients with CAD. The present results may partly explain the efficacy of DOAC on the reduced incidence of cardiovascular events in patients with CAD.
Abstract 10463: Angiotensin-Converting Enzyme 2 (ACE2) is Rate-limiting for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Infection in Beating Stem Cell-Derived Cardiomyocytes
Authors: Macrae Robyn G , Williams Thomas L , Colzani Maria T , Bloor Stuart , Zhan Jun Ru , Nyimanu Duuamene , Kuc Rhoda E , Maguire Janet J , Lehner Paul J , Sinha Sanjay , Davenport Anthony P
Published: March 2022

Introduction:
Cardiovascular comorbidities are a major risk factor in patients infected with SARS-CoV-2. SARS-CoV-2 Spike protein binds to host cell surface ACE2 to gain entry. ACE2 is subsequently downregulated by internalisation. We hypothesise that an ACE2 knockdown system in beating human embryonic stem cell-derived cardiomyocytes (hESC-CMs) will recapitulate the downregulation of ACE2, and reduce the ability of a SARS-CoV-2 Spike protein pseudotyped virus to infect these clinically relevant cells.

Method:
ACE2 was knocked down (KD) with CRISPR/Cas9 in hESCs, before differentiating to hESC-CMs and sub-culturing in 96 well plates. Sanger sequencing confirmed amino acid changes. Catalytic ACE2 activity was measured by mass spectrometry in wild-type versus KD by conversion of apelin-13 to apelin-12 in hESC-CMs supernatant. ACE2 activity was also measured by fluorescent substrate assay. Pseudotyped virus infection was visualised by high content screening in ACE2 KD versus wild-type (n=4). All data are mean±SEM.

Results:
Sequencing revealed two substitutions at ACE2
222-223
, and three deletions at ACE2
224-226
. This reduced ACE2 catalytic activity by ~60-70% by apelin-12 accumulation using mass spectrometry (Fig 1a), and fluorescent assay. Furthermore, KD reduced infection of hESC-CMs by pseudotyped virus to 27.3±9.6% of the cell population versus 74.8±4.7% for wild-type (Fig 1b,c). This is consistent with our previous data, showing DX600 (peptidic inhibitor of ACE2 catalytic site) significantly reduced infection of wild-type hESC-CMs to 20.5±6.5%.

Conclusions:
In conclusion, we generated a functional ACE2 knockdown in a beating cardiomyocyte cell model. Both the catalytic activity and the ability to bind SARS-CoV-2 Spike protein of ACE2 reduced, importantly indicating ACE2 is rate limiting for infection. We aim to use this system to further explore the cardiovascular consequences of SARS-CoV-2 infection and subsequent downregulation of ACE2.
Abstract 10464: Mental Health Conditions Are Associated with Underuse of Oral Anticoagulation Therapy in Patients with Atrial Fibrillation: The FinACAF Study
Authors: Jaakkola Jussi , Teppo Konsta , Airaksinen Juhani , Biancari Fausto , Putaala Jukka , Halminen Olli , Haukka Jari , Hartikainen Juha , Kinnunen Janne , Tiili Paula , Linna Miika , Mustonen Pirjo , Lehto Mika
Published: March 2022

Introduction:
Little is known about the effects of mental health conditions (MHC) on the utilization of oral anticoagulant (OAC) therapy in patients with atrial fibrillation (AF). We assessed the hypothesis that MHCs are associated with a lower rate of OAC initiation in patients with incident AF.

Methods:
The FinACAF registry included all 239 756 patients with incident AF during 2007-2018 in Finland identified from national registries covering all levels of care as well as their drug purchases. The main exposure was any MHC (previous diagnosis of depression, bipolar disorder, anxiety disorder or schizophrenia or fulfilled prescription of psychiatric medication within preceding year from first AF diagnosis) and the outcome OAC initiation (first fulfilled OAC prescription after AF diagnosis).

Results:
The patients’ mean age was 72.6 years (SD 13.2), 49.7% were female and 95.0% had CHA
2
DS
2
-VASc score ≥1. The prevalence of any MHC was 19.9%. A lower rate of OAC initiation was observed in patients with any MCH than in those without MHC (64.9% vs. 73.1%, p<0.001) during the entire follow-up. Any MHC was associated with lower cumulative incidence of OAC initiation (adjusted subdistribution hazard ratio (aSHR) 0.783; 95% CI 0.774-0.794, Figure) during the entire follow-up, as were depression (aSHR 0.833; 95% CI 0.813-0.852), bipolar disorder (aSHR 0.807; 95% CI 0.778-0.838), anxiety disorder (aSHR 0.816; 95% CI 0.758-0.878) and schizophrenia (aSHR 0.743; 95% CI 0.698-0.792) individually. By 2018, 89.9% of OAC initiations were with a non-vitamin K antagonist oral anticoagulant (NOAC) in patients with any MHC and 92.4% in patients with no MHC. Any MHC remained associated with impaired cumulative incidence of OAC initiation also in the NOAC-era during 2015-2018 (aSHR 0.821; 95% CI 0.805-0.837).

Conclusions:
MHCs are common among AF patients, and they are associated with a lower rate of OAC initiation even during the NOAC-era.
Abstract 10469: Cardiometabolic Risk Factors as Causal Mediators of the Relationship Between High Body Mass Index and Chronic Kidney Disease: A Two-Step Mendelian Randomization Study and Mediation Analyses
Authors: Emanuelsson Frida , Wade Kaitlin , Varbo Anette , Tybjaerg-hansen Anne , Davey Smith George , Nordestgaard Borge G , Benn Marianne , Timpson Nicholas
Published: March 2022

Introduction:
Observational studies suggest that obesity is a risk factor of chronic kidney disease (CKD). It is unclear whether this reflects a direct causal effect of obesity or an effect mediated by obesity-related metabolic changes.

Hypotheses:
We hypothesised that 1) obesity is a causal risk factor of CKD defined as eGFR <60mL/min/1.73m
2
and 2) this causal effect is mediated through changes in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterols, triglycerides, glucose, blood pressure and C-reactive protein (CRP) levels.

Methods:
To assess causality and investigate mediation, we used a combination of observational, two-step Mendelian randomization, and mediation analyses on individual-level data from two cohorts of the Danish general population (N=117,213).

Results:
Observationally, higher BMI was associated with a lower eGFR (change in eGFR; -0.81, confidence interval [CI]: -0.89- -0.73)) and a higher risk of CKD (odds ratio [OR]:1.19; 95% CI: 1.16-1.22) per 5kg/m
2
higher BMI (p for trend for both <2.9 x10
-40
). Mendelian randomization analyses supported a causal effect of higher BMI on lower eGFR (change in eGFR -17.3 mL/min/1.73m
2
(95%CI: -19.3- -15.3), and risk of CKD (risk ratio [RR]6.99 (95%CI: 1.63-30.1) per 5kg/m
2
higher BMI. Measured BMI and the BMI allele score used in Mendelian randomization analyses were associated with changes in levels of LDL and HDL cholesterols, triglycerides, glucose, blood pressure, and CRP. Observational and Mendelian randomization analyses showed evidence to support a causal effect of changes in levels of systolic and diastolic blood pressure, LDL cholesterol and CRP with lower eGFR and higher risk of CKD. Of the excess risk of CKD coming from high BMI, elevated systolic and diastolic blood pressure mediated 18%(95%CI:14-22) and 9% (7-11), respectively. 9% (95%CI: 8-12) was mediated by elevated LDL cholesterol and 29% (95%CI: 23-35) by elevated CRP.

Conclusion:
Triangulating evidence from observational and Mendelian randomization analyses provided evidence to support a causal role of obesity on the risk of CKD and that this causal effect may be partly mediated by elevated systolic and diastolic blood pressure, CRP and LDL cholesterol levels.
Abstract 10494: The Impact of Complete versus Partial Preservation of the Sub-Valvular Apparatus on Left Ventricular Function in Mitral Valve Replacement
Authors: Ng Yin Ling Clarissa , Bleetman David , Demir Fulya A , Eskandari Mehdi , Khan Habib , Baghai Max , Deshpande Ranjit , Monaghan Mark J , Wendler Olaf
Published: March 2022

Introduction:
In mitral valve replacement (MVR), sudden increase in afterload and disruption of the annular-chordal-papillary-left-ventricular wall causes LV dysfunction in the early postoperative period. Preservation of the posterior mitral leaflet apparatus (MVR-P) has a favourable outcome on LV function. However, there is paucity of data on the impact of complete preservation of the sub-valvular apparatus (MVR-C).

Objective:
We investigated the impact of MVR-P and MVR-C on baseline and 3-months postoperative LV ejection fraction (EF) and global longitudinal strain (GLS).

Methods:
We retrospectively analysed a cohort of 29 MVR-P and 19 MVR-C patients with complete echo data at our unit, who were operated between 2012-2017. Between-group changes in LVEF and GLS were compared using independent sample T-test.

Results:
Median age was 59 years (IQR 50-69 years). Baseline LVEF was 58% (51 - 60%). Baseline GLS was -18.4 (-21.2 - -15.5). There were no significant differences between all baseline demographics including age (p=0.45), underlying MV pathology (p=0.1), baseline LVEF (p=0.48) and GLS (p=0.15). There was significantly less worsening of GLS in MVR-C group as compared to the MVR-P group (p=0.023), indicating better preservation of LV function. There was also a lower decrease in LVEF in the MVR-C as compared to the MVR-P group, although the difference was not statistically significant (p=0.23).

Conclusion:
MVR with complete preservation of the sub-valvular apparatus shows a favourable impact on the longitudinal function of the heart at 3 months. Further studies with larger patient numbers are indicated to investigate the long-term results of this surgical approach.
Abstract 10495: Mechanism of Cardiac Repair in Rat Myocardial Infarction Model Treated with Extracellular Vesicles from Differentiating Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Tominaga Yuji , Miyagawa Shigeru , Kawamura Takuji , Ito Emiko , Takeda Maki , Nakae Masaro , Harada Akima , Sawa Yoshiki
Published: March 2022

Introduction:
A few reports showed the therapeutic effects of extracellular vesicles (EVs) secreted from induced pluripotent stem cell-derived cardiomyocytes (iPSCM) on animal ischemic cardiomyopathy models. However, the mechanism of the cardiac function restoration after EVs administration remained unclear. Then, this study aimed to identify the mechanism for the restoration of cardiac function after iPSCM-EVs treatment.

Methods:
We collected EVs from differentiating iPSCM (TnT positive > 80%) culture medium. Comprehensive miRNA-seq and proteome analysis in the EVs were performed.
In vitro
myocardial contraction assay and wound healing assay, and
ex vivo
aortic ring assay were performed.
In vivo
, we designed a rat model of myocardial infarction by left anterior descending artery (LAD) ligation and divided rats into two groups. Two weeks after LAD ligation, iPSCM-EVs (Group EV) or PBS (Group Ctl) were injected peri-infarct zone. We analyzed the sequential cardiac function, histological analysis, and comprehensive RNA sequence analysis of the border zone before the treatment and 3, 7, 14, and 28 days after the treatment (n=5 at each time point in each group).

Results:
EVs showed the potential of increased myocyte contraction velocity (11±0.7 vs 6.6±0.6 μm/s, mean±SD, p < 0.01) and enhanced endothelial migration
in vitro
and facilitated angiogenesis (46±6 vs 13±5 sprouting count, p=0.02)
ex vivo
.
In vivo
, Group EVs showed higher LVEF (57±5 vs 38±4 % at day28, p < 0.01) and smaller LVDd (6.8±0.3 vs 8.5±0.8 mm at day28, p < 0.01). Histological analysis showed a lower % fibrosis area in Group EV (22±6 vs 12±5 % at day28, p < 0.01) and significantly higher microvascular (vWF positive: 1.7 at day14 and 2.1 times higher at day28) and arterial (vWF and αSMA positive: 4.3 at day14 and 6.2 times higher at day28) density. RNA expression analysis showed the expression of HGF, SDF-1, and IGF-1 increased in Group EVs on day3 and 7. CTGF and collagen 1 increased in Group Ctl on day14 and 28.

Conclusions:
Intracardiac injection of iPSCM-EVs improved cardiac function in rat MI model via angiogenesis, increased myocyte contraction, and reduced fibrosis. Comprehensive expression analysis suggested the mechanism of action of EVs in cardiac repair.
Abstract 10497: Predictors of Poor Prognosis in Stable Coronary Artery Disease with and without N-Terminal Probnp Elevation
Authors: Martinez-milla Juan , Acena Alvaro , Gaebelt Hans P , Pello-Lazaro Ana M , Lopez-Castillo Marta , Gutierrez-Landaluce Carlos , Nieves Tarin , Huelmos Ana , Cristobal Carmen , Gonzalez-Casaus Maria L , lorenzo oscar , Kallmeyer Andrea , Canovas Ester , Alonso Joaquin , tunon Jose
Published: March 2022

Background:
Mineral Metabolism (MM) system and N-terminal probrain natriuretic peptide (NT-ProBNP) have been shown to add prognostic value in stable coronary artery disease (SCAD). However, the influence of NT-ProBNP on the prognostic role of MM in SCAD has not been shown yet

Methods:
We analyzed the prognostic value of MM markers (parathormone [PTH], klotho, phosphate, calcidiol [25-hydroxyvitamin D3], and fibroblast growth factor-23) in 964 pts. with SCAD and NT-ProBNP>125 pg/ml vs pts. with NT-ProBNP≤125 pg/ml included in five hospitals of Spain. The main outcome was the combination of death, heart failure, and ischemic events (any acute coronary syndrome, ischemic stroke, or transient ischemic attack).

Results:
622 pts. had NT-proBNP>125 pg/ml and 342 pts. had NT-ProBNP≤125 pg/ml. Median follow-up was 5.1 years. In the group of NT-proBNP>125 pg/ml patients were older, and there were more females and smokers than in pts. with normal NT-proBNP.In high NT-proBNP pts., the predictors of poor prognosis were PTH [HR=1.00 (1.00-1.00) p<0.001] and NT-proBNP [HR=1.006 (1.00-1.01) p=0.011], along with age [HR=1.039 (1.02-1.06) p<0.001], prior coronary artery by-pass graft [HR=1.624 (1.02-2.59) p=0.041], treatment with statins [HR= 0.315 (0.19-0.53) p<0.001], insulin [HR=2.490 (1.59-4.09) p<0.001], angiotensin receptor blockers [HR= 1.726 (1.16-2.56) p=0.007], nitrates [HR= 1.645 (1.10-2.45) p=0.014], and proton pump inhbitors [HR= 2.754 (1.74-4.36) p<0.001]. In the NT-proBNP≤125 pg/ml subgroup, poor prognosis predictors were plasma levels of non-high-density lipoprotein (non-HDL) cholesterol [HR=1.01 (1.00-1.02) p=0.014] and calcidiol [HR= 0.96 (0.92-0.99) p=0.045], as well as treatment with verapamil [HR=11.28 (2.54-50.00) p=0.001], and dihydropyridines [HR= 3.16 (1.63-6.13) p=0.001],

Conclusion:
In pts. with SCAD and NT-ProBNP>125 pg/ml, PTH and NT-ProBNP, that are markers related with ventricular damage, are predictors of poor outcome. In the subgroup of pts. with NT-ProBNP≤125 pgm/l, calcidiol and non-HDL cholesterol, more related to vascular damage, are the independent predictors of poor outcome. Then, in pts. with SCAD, baseline NT-ProBNP may influence the type of biomarker that should be used for risk prediction.
Abstract 10498: The Use of a Digital Telehealth Platform to Understand the Prevalence and Control of Cardiovascular Disease Risk and Risk Factors in the Indian Population - A Pilot Study
Authors: Vaishnav Aditi S , vaishnav sudhir
Published: March 2022

Introduction:
Despite the enormous & growing burden of CVD in India, there is still lack of awareness about the importance of guideline based prevention and risk factor control.

Objectives:
To understand the feasibility & utilization pattern of an open-to-public digital health (mHealth) platform designed to assess CVD risk, risk factors (RF), RF control and adequacy of prevention, and provide appropriate education and guidance based on the assessment.

Methods:
Data was collected over 2 months through the mHealth platform that was open to all adults aged 25-80 years. It was accessible at no cost via all web browsers on smart phones, computers & tablets with internet connectivity and was available in 2 languages.

Utilization of the platform was significantly higher in males - 93.7% (251/268) respondents. Therefore, the study population for this study comprised of 251 males (age 45.4
+
11.7 yrs). Females were not included due to the small sample size; hence the corresponding results will be published once adequate sample size is reached.

10 year CVD Risk was calculated using the Framingham Risk Score (FRS). RF, RF control and adequacy of prevention were assessed using national & international guidelines, as appropriate. Statin indicated conditions were atherosclerotic disease, diabetes mellitus, familial hyperlipidemia and FRS-CVD risk >=10%.

Results:
Results are summarized in Fig 1. Overall 186 subjects met the criteria of having statin indicated conditions; however, only 37.6% of them reported taking a Statin.

The commonest RFs were hypertension (68.5%) & sedentary lifestyle (57%). Rates of undiagnosed RFs were high -diabetes 45.7%, hypertension 20%, high normal BP 28%, and pre-diabetes 24.9%.

RF control was poor with only 23.2% of people with hypertension reporting BP <130/80, 38.9% of diabetics reporting HbA1c <7% and 26.2% of those taking Statins reporting LDL <70 mg/dL.

Conclusion:
The use of a digital health tool for CVD prevention is feasible and reveals a large unmet need.