bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10919: Prevalence, Awareness, Treatment, and Control of Hypertension in Hospitalized Patients with Atrial Fibrillation in China: Findings from the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation Project
Authors: Sun Zhaoqing , Hao Yongchen , Liu Jun , Yang Na , Huo Yong , Smith Sidney C , Ge Junbo , Fonarow Gregg C , Morgan Louise , Ma Chang-Sheng , Yaling Han , Zhao Dong , Liu Jing
Published: March 2022

Introduction:
Reports on the current status of hypertension control in patients with atrial fibrillation (AF) remain lacking in China. We aimed to provide the latest estimates on the prevalence, awareness, treatment, and control rates of hypertension and factors associated with uncontrolled hypertension in hospitalized patients with AF in China.

Methods:
Based on the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) Project, hospitalized patients with AF collected from 236 hospitals in 30 provinces of China between February 2015 and December 2019 were included in current analysis. The prevalence, awareness, treatment, and control rates of hypertension were estimated according to the Chinese Hypertension Guideline. Hypertension was defined as SBP ≥140mmHg or DBP ≥90mmHg measured at the time of admission, or a documented history of hypertension. Multivariable logistic regression was used to analyze the factors associated with uncontrolled hypertension (SBP ≥140 mmHg or DBP≥90mmHg).

Results:
A total of 61,136 hospitalized patients with AF were included, and the prevalence of hypertension was 66.1%. The awareness, treatment, and control rates of hypertension were 80.1%, 55.8%, and 39.9%, respectively. Among patients treated for hypertension, only 46% had their blood pressure controlled. The rates varied by patient characteristics and geographic regions (Table). Younger age (18-45 years of age), rural insurance, alcohol drinking, history of heart failure, mitral stenosis, pre-hospital use of antiplatelet drugs, valvular AF, new-onset AF, and Northeast China were associated with uncontrolled hypertension in patients with AF.

Conclusions:
Hypertension is common in hospitalized patients with AF. Although most patients are aware of this comorbidity, the treatment and control rates of hypertension are still low. The management of hypertension in patients with AF needs to be further strengthened.
Abstract 10920: Cost-Effectiveness of Pulmonary Vein Isolation with Epicardial Left Atrial Appendage Ligation for the Treatment of Non-Paroxysmal Atrial Fibrillation
Authors: Cheung Christopher C , Ferguson Michael , Anderson Louise H , Mittal Suneet , Lakkireddy Dhanunjaya R , Wilber David J , Lee Randall J , Dewland Thomas A
Published: March 2022

Introduction:
Electrical isolation of the left atrial appendage (LAA) using percutaneous epicardial ligation may improve catheter ablation outcomes for non-paroxysmal atrial fibrillation (AF) patients. Little is known regarding the cost effectiveness of this procedure.

Hypothesis:
We hypothesized that cost-effectiveness between pulmonary vein isolation (PVI) + LAA epicardial ligation using a percutaneous LARIAT
®
Suture Delivery Device would be cost effective (CE) compared to PVI alone over 5 years.

Methods:
A Markov model simulated outcomes for a population with annual stroke risk of 4.6% (CHA
2
DS
2
-VASc score 3). Model inputs for procedure efficacy, stroke and bleed events, health utility, and event costs were estimated from literature. Procedure costs from Medicare rates were used. The model had a 5-year time-horizon and US payer perspective. Univariate and probabilistic sensitivity analyses (PSA) were performed. Outcomes were health care costs and quality-adjusted life-years (QALYs). In the base case, PVI + LAA ligation efficacy from published studies was 67% after 1-year, with an estimated 25% oral anticoagulant (OAC) utilization in PVI + LAA ligation patients in normal sinus rhythm 13-60 months after the index procedure. Cost effectiveness thresholds were evaluated with alternative PVI + LAA ligation efficacy and OAC utilization rates, including 1-year PVI + LAA ligation efficacies of 67%, 70%, 75%, and 80% and OAC utilization of 20-60%.

Results:
In the base case, PVI + LAA ligation had a mean 5-year cost of $72,865 with 3.25 QALYs and PVI alone had mean cost of $69,936 with 3.19 QALYs. The incremental cost-effectiveness ratio was $46,716; PVI + LAA ligation was CE at $50,000 per QALY gained. In PSA, 64% and 82% of simulations were CE at $50,000 and $100,000 per QALY gained, respectively. In various scenarios, procedure efficacy of 75% combined with OAC utilization of 50% or below yielded CE at $50,000 per QALY gained. Reduction of OAC utilization to 30% yielded CE at $50,000 per QALY gained, regardless of efficacy.

Conclusions:
In the base case, PVI + LAA ligation was CE at $50,000 per QALY gained when compared to PVI alone. The CE threshold for efficacy was 75% and OAC utilization was 30%. Cost savings were driven by reductions in OAC use and increased efficacy.
Abstract 10928: Chlorogenic Acid Ameliorates Pressure Overload-Induced Cardiac Hypertrophy in Mouse Models
Authors: Morio Atsushi , satomi shiho , Miyoshi Hirotsugu , Toyota Yukari , Tsustumi Yasuo M
Published: March 2022

Introduction:
Cardiac hypertrophy leading to heart failure is one of the critical causes of morbidity and mortality. Although social interest in treatment and prevention of cardiovascular disease is high, sufficient outcome has not been obtained yet. Chlorogenic acid (CGA) is one of the most abundant phenolics in plants, and is called caffeic acid. Recently, the cardioprotective effects of CGA which ameliorate isoproterenol-induced hypertrophy in vitro research have been reported. However, it has not been elucidated whether CGA affects cardiac hypertrophy in vivo models with TAC.

Hypothesis:
We assessed the hypothesis that the administration of CGA has protective effect on TAC-induced cardiac hypertrophy.

Methods:
We used mouse models of cardiac hypertrophy induced by TAC for four weeks. Mice were randomly assigned to sham, TAC, and TAC+CGA groups. CGA was administered at dose of 40mg/kg intraperitoneally once a day for four weeks after the TAC operation. cardioprotective effect was investigated by echocardiography and histological analysises. In addition, immunoblot and metabolome analysises and biomedical assays were conducted in excised hearts. Statistical analysis was performed by one-way ANOVA. All data are expressed as mean ± SD. Statistical significance was defined as P < 0.05.

Results:
We evaluated sham group (n=8), TAC group (n=7), TAC+CGA group (n=7) four weeks after TAC operation. TAC group showed an increase of heart weight, which was attenuated by CGA (120.3±9.3mg, 148.8±9.0mg, 126.6±6.2mg, p<0.05). Consistently, echocardiography revealed that the change of myocardial diastolic wall thickness (0.79±0.1mm, 1.13±0.1mm, 0.93±0.1mm, p<0.05). Histological analysis indicated that fibrosis induced by TAC was alleviated by CGA. According to immunoblot analysis, TAC group showed overexpression of TGF-β, IL-6, and TNF-α. In addition, the enhancements of glycolysis and TCA cycle were indicated in metabolome analysis. These changes were modulated by CGA administration.

Conclusion:
In conclusion, the present study revealed that CGA administration ameliorates pressure overload-induced cardiac hypertrophy in rodent model. As a key factor, expression of inflammatory cytokines and modulation of glucose metabolism were observed.
Abstract 10933: Informal Caregivers’ Burden and Its Predictors in Heart Failure: A Mixed Methods Study
Authors: Durante Angela , Younas Ahtisham , cuoco angela , Zeffiro Valentina , Brawner Bridgette , Boyne Josiane , Juarez-Vela Raul , Vellone Ercole
Published: March 2022

Introduction:
Caring for relatives with heart failure is emotionally and physically intensive for informal caregivers leading to caregiver burden. Evidence also suggests that caregiver burden affects the quality of life of both components of the patient-caregiver dyad. Previous research provides a limited understanding of the nature of caregiver burden and its influencing factors from a dyadic perspective.

Hypothesis:
To develop a comprehensive understanding of caregiver burden, and to identify its predictors with a dyadic perspective

Methods:
A convergent mixed-method approach was used. In total, 184 patients with heart failure and their informal caregivers completed validated scales to measure burden, care dependency, quality of life, and social support and 50 caregivers participated also to a semi-structured interviews to better understand the caregiver experience. Multiple regression analysis was conducted to identify the predictors and qualitative content analysis was performed on qualitative data. The results were merged using joint displays.

Results:
Caregiver burden was predicted by patient worse cognitive impairment, lower physical quality of life, and a higher care dependency perceived by the caregivers. Qualitative and mixed analysis demonstrated that caregiver burden has a physical, emotional, and social nature. In particular time constraints, anticipated concerns about personal future, and generalized fatigue and exhaustion were significant predictors of caregiver burden, thereby affecting their caregiving.

Conclusions:
Caregiver burden can affect the capability of informal caregivers to support and care for their relatives with heart failure. There is a dire need for development and evaluation of individual and community-based strategies to address caregiver burden so as to enhance the quality of life of both caregivers and their relatives with heart failure.
Abstract 10935: Identification of Small-Molecule ERBB4 Agonists to Treat Heart Failure
Authors: Feyen Eline , Cools Julie , Van fraeyenhove Jens , Tubeeckx Michiel , Bruyns Tine , De Winter Hans , Audenaert Dominique , De Keulenaer Gilles W , Segers Vincent F
Published: March 2022

Introduction:
Heart failure is a complex syndrome with a poor prognosis. The neuregulin-1 (NRG1)/ERBB4 axis has been shown to be cardioprotective and is a possible target for heart failure therapy. Clinical trials with NRG1 are ongoing, but require intravenous administration. Our aim is to develop a small-molecule ERBB4 agonist with cardioprotective properties.

Methods:
A high-throughput diversity screening (HTS) of 10,240 compounds was performed on a cellular ERBB4/ERBB4 dimerization assay. Ligand binding of hit compounds was tested in co-administration studies with NRG1 (0.1 μM) and competition binding assays with fluorescently labeled NRG1 (0.03 μM). Selectivity, post-receptor phosphorylation, and cell toxicity of hit compounds were determined using Luminex® RTK phosphoprotein, U2OS ERBB2/ERBB3 dimerization and adenylate kinase assays. Biological effects were studied
in vitro
in different doses (4-32 μM) on TGF-β-induced collagen synthesis by human dermal and atrial fibroblasts, and on angiotensin II (AngII, 1000 ng/kg/min)-induced left ventricular (LV) remodeling in mice with 2 selected hit compounds (83 μg/kg/h), administrated through osmotic pumps (N=4-5/group). After 28 days, left ventricular myocardial fibrosis and cardiomyocyte cross sectional area (CSA) were analyzed.

Results:
The HTS resulted in 8 similar pyrimidine derivatives inducing ERBB4/ERBB4 but not ERBB2/ERBB3 dimerization (Emax 9 to 33% relative to NRG1, and EC50 6x10
-6
M to 2x10
-7
M). Two compounds were excluded due to
in vitro
toxicity. The other 6 compounds were non-toxic and induced ERBB4, but not ERBB1, ERBB2 or ERBB3 phosphorylation in EFO-21 cells. Competition assays showed allosteric binding, and co-administration studies with NRG1 revealed that compounds potentiated NRG1-induced ERBB4 receptor dimerization up to 2.5 fold. Selected compounds showed significant dose-dependent antifibrotic effects in cultured human atrial and dermal fibroblasts and significantly attenuated AngII-induced LV myocardial fibrosis by 76%±26%, whereas cardiomyocyte CSA was not affected.

Conclusions:
We identified novel pyrimidine derivative small-molecule ERBB4 agonists with antifibrotic properties, both
in vitro
and in a mouse model of AngII-induced LV fibrosis.
Abstract 10940: Leptin Treatment Protects the Endothelium from Inflammation, Increased Permeability and Endothelial-to-Mesenchymal Transition
Authors: Schubert Marie R , Stuerzebecher Paulina , Kralisch Susan , Hoffmann Annett , Bluher Matthias , Fasshauer Mathias , Laufs Ulrich , Tönjes Anke , Boeckel Jes-Niels
Published: March 2022

Introduction:
Patients with lipodystrophy (LD) are characterized by a loss of adipose tissue and are associated with a higher risk for cardiovascular diseases (CVD). As a consequence of adipose tissue reduction in LD patients, the systemic concentration of the adipokine leptin decreases, representing the pathological cause of this disease.

Hypothesis:
We hypothesized that the reduction of leptin may impair endothelial cells, leading to the development of CVD. Therefore, we analyzed the effects of leptin treatment on vascular inflammation, endothelial-to-mesenchymal transition (EndMT), endothelial permeability and atherosclerotic plaque characteristics.

Methods & Results:
Treatment of endothelial cells with leptin (200 ng/ml, 6 h) potently reduced IL1β-induced inflammation, as measured by expression of ICAM1 (-25.1%) and E-Selectin (-22.7%), (both p<0.05). Leptin further reduced the induction of EndMT, as determined by expression of calponin (-41.3%) and SM22 (-23.8%), (both p<0.05), as well as the EndMT-induced endothelial permeability (-20.7%, p<0.05). These data were confirmed in a combined lipodystrophic and atherosclerosis prone mouse model (LDLR
-/-
;aP2-nSREBP). Treatment with leptin (3.0 mg/kg) for 8 w reduced the number of EndMT-positive endothelial cells (-69%, p<0.05) as well as the total number of mesenchymal cells in the atherosclerotic lesions (-34.8%), (both p<0.05). Further analysis of the atherosclerotic lesions revealed a reduction of atherosclerotic plaque protrusion into the vessel lumen (-31%) and reduced macrophage infiltration (-21.9%) (p<0.05), which is a hallmark of instable atherosclerotic plaques that are prone to rupture, whereas the total plaque area was not affected. The expression of the leptin receptor (LepR) was reduced in endothelial cell inflammation, EndMT (-69%, p<0.05) and in atherosclerotic lesions, suggesting reduced leptin effects under these conditions.

Conclusions:
Leptin treatment exerts beneficial effects protecting endothelial function and identity in lipodystrophy. Downregulation of the leptin receptor in diseased endothelial cells is likely to reduce the identified positive vascular effects of leptin signaling in lipodystrophy.
Abstract 10943: Deep Vein Thrombosis Frequency at Acute Stroke Admission
Authors: Mori Takahisa , Yoshioka Kazuhiro , Miyazaki Yuichi
Published: March 2022

Introduction:
Intermittent pneumatic compression (IPC) is used to prevent deep vein thrombosis (DVT) during hospitalization in patients with acute stroke. However, if existing DVT is not examined during admission, IPC massage of the legs with DVT may cause migration of the thrombi.

Hypothesis:
The frequency of DVT at acute stroke admission is high and significant factors indicate the presence of DVT at acute stroke admission.

Methods:
We included patients admitted within 24 hours of stroke onset, between 2017 and 2019. We collected patient data on age, sex, anthropometric variables, DVT presence by whole-leg ultrasonography, and biomarkers such as D-dimer and lipids.

Results:
Of 1129 stroke patients, 907 met our inclusion criteria. DVT was detected in 159 patients (17.5%). Compared to patients without DVT (n=748), patients with DVT were older, females, with lower body weight, higher D-dimer and C-reactive protein levels, lower albumin or triglyceride (TG) levels, and higher National Institutes of Health Stroke Scale score. Multiple logistic regression analysis showed that sex, D-dimer, and TG were independent DVT-presence variables.

Conclusions:
DVT occurred in 17.5% of acute stroke patients at admission, and significant DVT-presence factors were female sex, high D-dimer level, and low TG level. Patients with the three significant factors at admission must immediately undergo whole-leg ultrasonography to detect DVT.
Abstract 10945: Risk Stratification and Prediction of Acute Myocardial Infarction Events Patients of Connective Tissue Disorders
Authors: Gad Mohamed M , Abdelfattah Omar M , Bansal Agam , Isogai Toshiaki , Chatterjee Soumya , Cremer Paul , Kapadia Samir R , Menon Venu , wassif heba
Published: March 2022

Introduction:
Connective tissue disorders (CTD) play an important role in the pathogenesis of atherosclerotic heart disease with a dynamic interplay between inflammatory and traditional cardiovascular risk factors.

Hypothesis:
We aim to develop, validate, and compare population-level machine learning models to predict the first acute myocardial infarction (AMI) event in CTD.

Methods:
We extracted patient data from the Healthcare Cost and Utilization Project (HCUP) and identified 62 demographic and clinical variables. We identified those with systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, mixed connective tissue disorder, Sjogren’s syndrome, polymyositis, and dermatomyositis. We excluded those with prior history of myocardial infarction, known coronary artery disease, or missing key variables. We split the records randomly into training (70%) and testing (30%) datasets. Keras sequential model with Adadelta optimizer was used to compile the deep neural network model and scikit-learn classifiers were used for machine learning models. We estimated model performance based on the area under the receiver-operator characteristics curve (AUC).

Results:
961,405 records were identified, and out of these, 14,961 (1.6%) had the first AMI event. The neural network model performed best in predicting AMI with an AUC:0.96 [A]. Classifier models had varying degrees of success range from 0.71 to 0.86 with Gradient Boosting Classifier, AUC:0.86 [B], being the best performing classifier, followed by Decision Tree, AUC:0.85, Logistic regression, AUC:0.84, Random Forest, AUC:0.84, Naive Bayes, AUC:0.75, Stochastic Gradient Descend, AUC: 0.71.

Conclusions:
A neural network model was able to predict the first AMI in people with CTD accurately. Developing and implementing machine learning models can help clinicians predict individual patient risk with a high degree of success.
Abstract 10947: Sacubitril/Valsartan versus Spironolactone in Heart Failure with Preserved Ejection Fraction; A Cost per Outcome Analysis
Authors: Tsaban Gal , Alnsasra Hilmi , Abu-Dogosh Ala , Weissberg Itai , Golan Yael , Barrett Orit , Westreich Roi , Aboalhasan Enis , Azuri Joseph , Hammerman Ariel , Arbel Ronen
Published: March 2022

Introduction:
Heart failure with preserved ejection fraction (HFpEF) is associated with frequent hospitalizations and an increased risk of death. There are no therapies with certain benefits for the treatment of HFpEF. Spironolactone and Sacubitril/Valsartan have shown marginal significance benefits in HFpEF and are approved to treat this condition. We aimed to compare the value for money of these treatments.

Hypothesis:
Spironolactone provides better value for money than Sacubitril/Valsartan for preventing HF events in patients with HFpEF.

Methods:
We compared the cost needed to treat (CNT) to prevent the composite outcome of HF hospitalization and CV death with Spironolactone or Sacubitril/Valsartan. The CNT was estimated by multiplying the annualized number needed-to-treat (aNNT) by the annual cost of therapy. The aNNTs were calculated based on data from the TOP-CAT and PARAGON trials. Costs were based on 2021 US prices. Scenario analyses were performed to attenuate the differences in the studies’ populations. Subgroup analyses were performed for mildly reduced EF.

Results:
The aNNT to prevent the composite outcome with Sacubitril/Valsartan in PARAGON was 53 [95% CI:28-∞] versus 107 (95% CI:51-∞), with spironolactone in TOPCAT. At an annual cost of $5,100 versus $1,353, The corresponding CNTs were $270,273 (95% CI:142,786-∞) for Sacubitril/Valsartan and $144,773 (95% CI:69,004-∞) for spironolactone. Figure 1 illustrates the results of the scenario and subgroup analysis.

Conclusion:
Despite lower clinical efficacy, spironolactone provides better value for money than Sacubitril/Valsartan in preventing HF hospitalizations and cardiovascular death among patients with HFpEF.
Abstract 10948: Post-Infarct Cardiac Remodeling Predictions with Machine Learning
Authors: Dieu Xavier , Chabrun Floris , PRUNIER FABRICE , Reynier Pascal , Furber Alain p , Garcia Gabriel , Bière Loïc , Mirebeau-Prunier Delphine
Published: March 2022

Introduction:
We sought to improve the risk prediction of 3-month left ventricular remodeling (LVR) occurrence after myocardial infarction (MI), using a state-of-the-art machine learning approach.

Methods:
We retrieved 135 variables, ranging from clinical, biological and cardiac magnetic resonance data, from 379 patients with ST-elevated myocardial infarction and processed them with a machine learning pipeline using advanced feature selection and modelling algorithms such as gradient boosting, neural networks or recurrent neural networks.

Results:
A baseline logistic regression model using known variables such as infarct size, creatine kinase peak, no reflow and cardiovascular risk factors, achieved an AUC of 0.71 on the test, with 67% sensitivity and 64 % specificity. In comparison, our best predictive model was a neural network using seven variables (in order of importance): creatine kinase, mean corpuscular volume, baseline left atrial surface, history of diabetes, history of hypertension, red blood cell distribution width, and creatinine. This model achieved an AUC of 0.78 on the test set, reaching a sensitivity of 92% and a specificity of 67%, outperforming the baseline model.

Conclusions:
We were able to achieve state-of-the-art performance with a high level of sensitivity for the prediction of a 3-month post-MI LVR. Our unbiased data-driven machine learning approach highlights the role of classical parameters alongside unexpected variables such as left atrial dilation at baseline, mean corpuscular volume and red blood cell distribution width whose role in the pathophysiology of post-MI cardiac remodeling remain to be clarified. The relative simplicity and the good availability of these parameters make our new approach suitable for clinical testing.
Abstract 10957: Inflammation: A Window into the Pathobiology of Impaired Vascular Regeneration in Patients with Coronary Artery Disease
Authors: Almuwaqqat Zakaria , Kim Jeong Hwan , Garcia Mariana , Alkhalaf Jamil , Mehta Anurag , Shah Amit J , Pearce Brad , Bremner Doug , Waller Edmund , Vaccarino Viola , Quyyumi Arshed A
Published: March 2022

Introduction:
The mechanisms by which cardiovascular regenerative capacity, estimated as circulating levels of progenitor cell (CPC) counts, protect against adverse cardiovascular events remain unclear.

Hypothesis:
Circulating progenitor cells possess immune-modulatory properties and are hypothesized to mitigate inflammation that is characteristic of patients with CAD. We hypothesized that patients with fewer CPC will have higher inflammatory markers and worse outcomes.

Methods:
Patients with stable CAD were enrolled in a prospective study enumerating CPCs as CD34-expressing mononuclear cells (CD34+), and inflammation as levels of interleukin-6 (IL-6). Patients were followed for 5 years for the endpoints of death and myocardial infarction (primary) with repeat inflammatory biomarkers measured after a median of 2 years. The association between CPCs and change in IL-6 levels over time was determined using linear regression after adjustment demographic and clinical risk factors. Cox hazard models were used for time-to-event analyses after adjustment.

Results:
In the entire cohort of 392 patients, IL-6 remained unchanged (0.3 ± 2.4 pg/mL, p=0.45) after 2 years. CPC counts (log-transformed) were inversely correlated with the change in IL-6 levels (r=- 0.17, P <0.001). Thus, IL-6 declined by - 0.59 ((95%CI), -0.90, -0.20) pg/mL per 1 log higher CPC counts after adjustment for the demographic and clinical variables as well as medications. Using Cox hazard models adjusted for these risk factors, a rise in 1 pg/mL of IL-6 was associated with a 11% (95%CI, 9, 13) greater risk of death/MI. Low CPC counts were associated with a higher risk of death/MI (HR=1.7 (95%CI, 1.1-2.6). Using mediation analysis, we found that the change in IL6 level partly (by 40%) mediated the higher risk of adverse events among those with low CPC counts.

Conclusions:
Reduced cardiovascular regenerative capacity, measured as low circulating CPC levels, is independently associated with progressive inflammation in patients with CAD, which in turn is associated with poor outcomes. These findings support the role of endogenous regenerative capacity in passivating systemic inflammation and is a potential mechanism underlying its protective effects.
Abstract 10960: Genetic Overlap of Acute Myocarditis and Inherited Cardiomyopathy
Authors: Lota Amrit S , Hazebroek Mark , Theotokis Pantazis , Wassall Rebecca , Salmi Sara , Halliday Brian , Tayal Upasana , Verdonschot Job , Meena Devendra , de Marvao Antonio , Iacob Alma , Hammersley Daniel , Jones Richard , Wage Rick , Buchan Rachel , Yazdani Momina , Noseda Michela , Mittal Tarun , Wong Joyce , Robertus Jan Lukas , Baksi John , Vassiliou Vassilios , Tzoulaki Ioanna , Pantazis Antonios , Cleland John , Barton Paul J , cook stuart , Pennell Dudley J , Garcia-Pavia Pablo , Cooper Leslie T , Heymans Stephane , Ware James S , Prasad Sanjay K
Published: March 2022

Background:
Myocarditis may predispose to dilated cardiomyopathy (DCM) and sudden cardiac death (SCD). Familial data indicate a potential genetic susceptibility shared with arrhythmogenic cardiomyopathy (ACM). We present the first large-scale genotype-phenotype study of adults with acute myocarditis.

Methods:
A cohort comprising 336 consecutive patients with acute myocarditis was enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterised cardiomyopathy-associated genes. The burden of rare protein altering variants (PAV) in ACM genes, DCM genes, and TTN specifically, were compared with local healthy controls sequenced on the same platform (n=1053). Case ascertainment was assessed against national hospital admission data.

Results:
We identified rare protein-altering variants in 23% of cases compared to 16% in controls (Δ+6.8%; p=0.021), with rare truncating variants (tv) in 6% of cases compared to <1% of controls ((Δ+5%; p=0.0097). In London (n=230; median left ventricular ejection fraction (LVEF) 63%), which was representative of national myocarditis admissions, 4.8% of cases carried rare tv, particularly within ACM genes (3% cases vs 0% controls; odds ratio 8.2; p=0.001). This was predominantly driven by desmoplakin (DSP)-tv in patients with normal LVEF. In Maastricht (n=106; median LVEF 30%), rare tv in DCM genes were enriched, particularly TTN-tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). During a median follow-up of 1.9 years, all-cause mortality was greatest in those with a DCM variant (18% vs 4% with no variant; OR 5.0; p=0.004).

Conclusion:
We identified enrichment of cardiomyopathy gene variants in acute myocarditis patients, dominated by DSP-tv in those with normal LVEF and TTN-tv in those with reduced LVEF. Incorporation of genetic testing may be beneficial to identify such high-risk individuals and guide family screening in acute myocarditis patients.
Abstract 10971: Prevalence and Risk Factors of Silent Brain Microbleeds in Patients with Severe Valvular Heart Disease
Authors: Watanabe Tomohiko , Kanzaki Yumiko , Yokoyama Ryo , Hoshiga Masaaki
Published: March 2022

Introduction:
The presence of cerebral microbleeds (CMBs) has been described using MRI in patients with cardiovascular risk factors or prior stroke and could predict future cognitive dysfunction or cardiovascular mortality. CMBs are highly frequent (> 50%) in patients with infective endocarditis (IE). However, the association of CMBs and clinical factors in patients' valvular disease without IE remains unclear.

Hypothesis:
Valvular heart disease without IE confers a risk factor for microbleeds.

Methods:
We retrospectively examined data from the consecutive 96 patients ( 72 ± 9 years, 49 men) with severe valvular disease who underwent T2*-weighted brain MRI before cardiac surgery. The patients with neurological abnormalities or IE were excluded. Conventional echocardiography was performed to evaluate the left ventricular volume and valvular abnormalities. CMBs were coded by researchers blind to clinical details, who independently assessed the presence and location of CMBs using a standardized form. The study population consisted of 59 patients with severe aortic stenosis (AS) (group A) and 40 patients with severe aortic or mitral regurgitation (group B).

Results:
CMBs were found in 26 patients (27%), 14 (15%) had multiple CMBs. CMBs were most frequently seen in the lobar locations (69%), followed by deep or infratentorial locations (62%). No significant relationship was found between CMBs in dyslipidemia, diabetes mellitus, smoking status, anticoagulant, and antiplatelet therapy in both groups. In group A, the HAS-BLED score was higher in patients with CMBs, and the presence of CMBs was associated with hypertension (P<0.05); however, no significant differences were observed in the left ventricular mass index (LVMI), LV end-diastolic volume (LVEDV), any aortic valve severity parameters. In group B, there were significant differences in LVMI and LVEDV between patients with CMBs and those without (154 ± 40 g/m
2
vs 125 ± 32 g/m
2
, P < 0.01 ; 150 ± 39 ml vs 111 ± 38 ml, P<0.01).

Conclusion:
CMBs were frequently observed in severe valvular heart disease without IE. The presence of CMBs was independent of antiplatelet or anticoagulant therapy. In aortic or mitral regurgitation patients, LV remodeling may contribute to the development of CMBs.
Abstract 10973: Tenascin-C Deficiency Rescues the Effect of Diabetes on Cardiac and Vascular Dysfunction in Mice
Authors: K Attila , Arnold Zsuzsanna , Aykac Ibrahim , Acar Eylem , Szabó Petra L , Fee Alexander , Szekeres Maria , Watzinger Simon , Nádasy György , Hamdani Nazha , Podesser Bruno K
Published: March 2022

Introduction:
Tenascin-C (TN-C) upregulation is linked to worse clinical outcome in diabetic patients. However, the role of TN-C in the development of diabetic cardiomyopathy is still unknown.

Hypothesis:
Whether TN-C plays a maladaptive role in diabetic cardiomyopathy.

Methods:
AJ (n=14) and TNC-KO (n=16) adult male mice were injected with streptozotocin (50mg/kg) to induce diabetes. Cardiac function was measured by echocardiography at 16-18 weeks follow-up. Additionally, cardiomyocyte passive stiffness , vascular endothelial function (aorta), and cardiac fibrosis were assessed. In addition, the hemodynamic effect of human recombinant TN-C (hrTN-C; 80 ng/ml) on the isolated working rat heart (n=3) was evaluated. Isolated primary mouse cardiomyocytes (IPMC) were used to assess TN-C expression. Human ventricular cardiac fibroblasts (HCF) were cultured and treated with 1) TGF-β (20ng/ml); 2) rhTN-C (10μg/ml) and TLR4 inhibitor (TAK-242, 50 mM) in combination with TN-C and mRNA expression of α-SMA, TN-C, Col-1, Col-3 and ACE1 were assessed by RT-qPCR. Finally, HUVEC were treated either with rhTN-C (10μg/ml) or combination with TLR-4 inhibitor and analysed of the expression of NADPH oxidase 1 and 4 (NOX1, NOX4).

Results:
TN-C deficiency was accompanied by preserved LV ejection fraction and endothelium function in aorta (p<0.05, respectively). Diabetic TN-C KO mice show reduction in cardiomyocyte stiffness and diastolic dysfunction as compared to AJ diabetic group (p<0.01). Histology revealed less cardiac and perivascular fibrosis in diabetic TN-C KO animals than in the AJ diabetic group (p<0.01). In addition, rhTN-C resulted in reduction in cardiac function in isolated rat hearts. mRNA expression of TN-C was increased in IPMC. Moreover, TGF-β treatment markedly upregulated TN-C expression (p<0.01) and rhTN-C promoted pro-fibrotic genes expression (p<0.05, respectively). HUVEC incubated with rhTN-C showed increased expression of IL-6 and NOX4 via TLR-4 signalling.

Conclusions:
TN-C promotes a hostile environment that facilitates fibrosis and oxidative stress leading to cardiomyocyte and endothelial cell dysfunction. Thus, TN-C may play a crucial role in cardiovascular dysfunction in diabetes as well as a potential target for therapy.
Abstract 10974: Durable Reductions in Circulating Angiotensinogen and Blood Pressure Six Months After Single Doses of ALN-AGT, an RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, in Hypertensive Patients
Authors: Huang Stephen , Taubel Jorg , Casey Sarah , Leung Pui Man , Webb David J , Desai Akshay S , Cheng Yansong , Rhyee Sean , Harrop Jamie , Habtemariam Bahru , Bakris George L
Published: March 2022

Introduction:
ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, is being evaluated as a novel treatment for hypertension in a multicenter, randomized, placebo-controlled single ascending dose study. Here we present new data on the long-term pharmacodynamic and antihypertensive effects of ALN-AGT six months after single-dose administration.

Methods:
As part of a Phase 1 program to assess the safety and tolerability of ALN-AGT, hypertensive patients (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after a washout of antihypertensive medications) were randomized 2:1 to ascending single doses of ALN-AGT (10-800 mg) or placebo. Change from baseline BP was measured by ambulatory BP monitoring (ABPM) at Week 8, Week 12, and Month 6. Interim results as of May 28, 2021 are reported.

Results:
84 hypertensive patients (mean age 53 years, 61% male, 26% black, mean (SD) baseline 24-h SBP 140 (9) mm Hg) were enrolled in ascending single dose cohorts of ALN-AGT up to 800 mg SC. Dose-dependent and durable reductions in serum AGT levels were observed, with single doses ≥100 mg achieving serum AGT reductions >90% and 24-h SBP reductions >10 mm Hg (17 mm Hg in the 800 mg cohort) through Week 12. The 24-hour ABPM profile of ALN-AGT-treated patients showed sustained reductions of daytime BP with equally marked nighttime BP reduction. Notably, new data from follow-up visits show that all patients who received a single dose of 800 mg maintained serum AGT reductions >90% from Week 3 to Month 6, with a mean (SD) 24-h SBP reduction of 22 (15) mm Hg at Month 6 (5 of 8 patients without add-on antihypertensive treatment). There were no treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium. No patient required intervention for hypotension.

Conclusions:
Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in profound reductions in serum AGT and BP through Month 6. The durable reduction of serum AGT >90% with sustained 24-hour BP reduction over a period of 6 months after single dose SC administration of ALN-AGT 800 mg supports further evaluation of both quarterly and biannual dose administration.
Abstract 10979: Liver-Humanized Mice Provide a New Platform to Study Human Cardiometabolic Diseases
Authors: Minniti Mirko E. , Foquet Lander , Pedrelli Matteo , Gierer Emilia , Goldman Devorah , Copenhaver Robert , Luquet Serge H. , Grompe Markus , Paolo Parini
Published: March 2022

Introduction:
Conventional mouse models do not fully recapitulate human cardiometabolic diseases (CMD),
e.g.
, atherosclerosis and nonalcoholic steatohepatitis (NASH), due to species differences in metabolism. Liver-humanized mice (LHM),
i.e.
, mice repopulated with human hepatocytes, have been shown to be an improved translatable model to study human hepatic and lipoprotein metabolism.

Hypothesis:
As dietary challenge is often used to induce CMD in animal models, we sought to characterize lipoprotein and lipid metabolism in LHM challenged by different diets.

Methods:
Immune-deficient FRGN mice receiving hepatocytes from different human donors (LHM) or NOD mouse (liver-murinized mice, LMM) were fed a high-fat/high-sucrose diet (HFHSD) for 8 weeks or a high-fat/high-fructose/high-cholesterol diet (NASH-diet) for 8, 12, 16 or 20 weeks. Plasma lipids and lipoproteins were quantified after size-exclusion chromatography separation or by routine clinical assays. Cholesterol in the descending aorta was analyzed by GC-MS. Histologic analysis of hearts or livers was done using hematoxylin/eosin or Oil Red O staining, and anti-mouse CD68-antibody was used to detect murine macrophages.

Results:
Compared with LMM, LHM fed either HFHSD or NASH-diet accumulated plasma cholesterol and triglycerides within LDL and triglyceride-rich particles (VLDL and remnants). However, only the NASH-diet induced a notable hyperlipidemia and a substantial increase in cholesteryl esters within the aorta. NASH-diet also determined a clear accumulation of neutral lipids and CD68-positive cells in the aortic valves of LHM. Similarly, hepatocyte ballooning, liver steatosis and fibrosis were also induced by the NASH-diet. All these pathologic changes occurred during diet challenge at different time points.

Conclusions:
LHM developed severe hyperlipidemia, atherosclerosis and NASH when fed a NASH-diet, but not on HFHSD. The high quantity of cholesterol in the NASH-diet likely compensates for the high utilization of cholesterol of LHM due to their known increase in bile acid synthesis, prompting dyslipidemia and CMD. LHM fed a NASH-diet is an improved model for human CMD and for the development of therapeutic strategies rapidly translatable to the human condition.
Abstract 10984: The Novel Curcumin Formulation, ASD-Cur Suppressed Myocardial Infarction Induced Heart Failure in Rats
Authors: Takai Hidemichi , Morimoto Tatsuya
Published: March 2022

Introduction:
Curcumin prevents the development of heart failure, demonstrating that the compound is a potential treatment for the disease. Although curcumin is known to be safe, its therapeutic efficiency is limited due to its low bioavailability. To overcome this problem, we developed ASD-Cur, an amorphous formulation of curcumin.

Hypothesis:
ASD-Cur have greater therapeutic potency than Theracurmin
®
, a colloidal submicron dispersion of curcumin.

Methods:
Male SD rats were orally administrated with ASD-Cur or Theracurmin
®
(10 mg/kg curcumin). The plasma levels of curcumin were measured at 0.25, 0.5, 1, 2, 4 and 6 hours after administration. Twelve healthy volunteers, who had provided written informed consent, were administrated with ASD-Cur or Theracurmin
®
containing 30 mg curcumin, and plasma curcumin concentrations were determined at 0.5, 1, 2, 4 and 8 hours. Next, the rats were subjected to MI or sham surgery. One week after surgery, the MI rats were randomly assigned to 4 groups: vehicle, ASD-Cur (0.2 mg/kg curcumin), or Theracurmin
®
(0.2 or 0.5 mg/kg curcumin). Daily oral administration of these compounds was repeated for 6 weeks. After echocardiographic examination, myocardial cell diameter, perivascular fibrosis, mRNA levels, and the acetylation of histone H3K9 were measured.

Results:
After administration, the area under the plasma concentration-time curve (AUC
0-6h
) and the maximum plasma concentration (C
max
) of ASD-Cur were 3.7-fold and 9.6-fold higher than those of Theracurmin
®
, respectively. The AUC
0-8h
and C
max
of ASD-Cur in humans were 3.4-fold and 5.4-fold higher than those of Theracurmin
®
, respectively. Echocardiographic analysis showed that 0.2 mg/kg ASD-Cur and 0.5 mg/kg Theracurmin
®
significantly improved both MI-induced reduction in FS and left ventricular hypertrophy to the same extent. Both treatments significantly suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers and cardiac fibrosis, and the acetylation of histone H3K9 to the same extent.

Conclusions:
These findings indicated that ASD-Cur has greater bioavailability than Theracurmin
®
, and could have greater therapeutic potency towards MI-induced heart failure at a lower dose.
Abstract 11002: Assessing Widening Disparities in Hba1c and Systolic Blood Pressure Re-Testing During the Covid-19 Pandemic in LGBTQ+ Focused Federally Qualified Health Centers in Chicago
Authors: Rivera Adovich , Plank Megan , Feinstein Matthew J , Rusie Laura , Beach Lauren B
Published: March 2022

Introduction:
The COVID-19 pandemic caused disruptions in the health services delivery, especially among vulnerable populations. We assessed if the pandemic widened disparities in care for cardiometabolic conditions in a LGBTQ+-focused federally qualified health system in Chicago.

Hypothesis:
Disparities in monitoring cardiometabolic conditions present in 2019 worsened in 2020.

Methods:
We analyzed electronic health records from Howard Brown Health. We assessed HbA1c re-testing and control (≤9%) in 2019 and 2020 among people with diabetes (DM) and ≥1 HbA1c test in the prior year (2018 for 2019, 2019 for 2020) (n2019=818, n2020=1033). A similar assessment was done for hypertension (HTN) with systolic blood pressure (SBP) (n2019=2813, n2020=3660). Comparisons per demographic group per year were done using logistic regression adjusting for socio-demographic variables.

Results:
Re-testing rates declined from 2019 to 2020 for both HbA1c and SBP overall and across all groups. Adjusted analysis showed gay people with DM had higher rates of HbA1c re-testing than people of other sexual orientations in 2019 and experienced a significantly lower re-testing rate decline in 2020. Adjusted analysis for SBP showed that white (vs Hispanic) and straight (vs gay) people with HTN had lower SBP re-testing rates in 2019 and 2020.

Rates of controlled SBP (<140mmHg), but not HbA1c (≤9%), declined from 2019 to 2020. Adjusted analyses showed that straight (vs gay) patients had lower controlled HbA1c and SBP rates. Cis males (vs trans males) had lower controlled SBP and white (vs Asian/other) had lower controlled HbA1c. These disparities did not worsen in 2020.

Conclusion:
The pandemic had mixed impacts on cardiometabolic service disparities in a large LGBTQ+-focused health system. Disparities by sexual orientation for HbA1c widened during the pandemic. Similar worsening was not found for systolic blood pressure, nor for other demographic groups.
Abstract 11004: Activated Protein C Protects Human Cardiomyocytes Against Hypoxia Reoxygenation Stress-Induced Injury Through Maintaining Mitochondrial Integrity
Authors: Davitt Kayla , Fedorova Julia , Le Van , Logan Cole , Yang Yi , Ren Di , Li Ji
Published: March 2022

Introduction:
Activated protein C (APC) is a vitamin-K-dependent plasma serine protease that functions as a natural anticoagulant to downregulate thrombin generation in the clotting cascade. Endothelial protein C receptor (EPCR) mediates APC's cytoprotective properties. We found that cardiac EPCR expression is downregulated in aging, leading to cardiac intolerance to ischemic insults. However, the role of APC in the human heart under ischemic stress remains unclear.

Hypothesis:
APC-EPCR axis protects human cardiomyocytes against hypoxia-reoxygenation stress-induced damage through maintaining mitochondrial integrity.

Methods:
The left ventricles of 38 adult human donor hearts underwent proteomic analysis of myocardial EPCR. Viable human cardiomyocytes were isolated and challenged by 30 min hypoxia/30 min reoxygenation (H/R) with or without APC treatment. Cardiomyocyte contractile properties were determined by IonOptix Imaging System, while the mitochondrial functional integrity and reactive oxygen species (ROS) were determined with Seahorse XF analyzer and MitoSox staining.

Results:
Immunoblotting data demonstrated that EPCR expression levels are declined in human hearts along with aging. H/R-stress reduced contractile functions of human cardiomyocytes, and the cardiomyocytes from aged adults (>65 years) versus cardiomyocytes from young adults (<65 years) were more vulnerable to H/R-induced insults. Interestingly, the administration of APC significantly improved the contractile functions of both young and aged human cardiomyocytes under H/R stress. APC also stabilizes EPCR levels and modulates the calcium flux homeostasis in both young and aged human cardiomyocytes under H/R. The mitochondrial respiration experimental data demonstrated that APC treatment ameliorates the mitochondrial dysfunction induced by H/R stress in both young and aged human cardiomyocytes. Since the ROS generations in human cardiomyocytes during H/R stress were attenuated with APC administration.

Conclusions:
Cardiac EPCR levels are downregulated with aging. The administration of APC can rescue the cardiac intolerance to ischemic insults in aging through stabilizing receptor EPCR and maintaining cardiomyocyte mitochondrial integrity.
Abstract 11006: Prevalence and Hemodynamic Profiles of Pulmonary Hypertension in Cardiac Amyloidosis
Authors: Slivnick Jeremy , Zareba Karolina , Varghese Juliet , Truong Vien , Wallner Alexander , Tong Matthew S , Hummel Christopher , Mazur Wojciech , Rajpal Saurabh
Published: March 2022

Background:
While cardiac amyloidosis (CA) classically involves the left ventricle (LV), less is known about its impact on the right ventricle (RV) and pulmonary vasculature.

Objectives:
We aimed to determine the prevalence and types of PH profiles in CA, and to determine hemodynamic and cardiovascular magnetic resonance (CMR) predictors of major adverse cardiovascular events (MACE).

Methods:
CA patients who underwent CMR and right heart catheterization (RHC) from 2010-2019 were included. Patients were assigned the following hemodynamic profiles: no PH, pre-capillary PH, isolated post-capillary PH (IPCPH), or combined pre- and post-capillary PH (CPCPH). Transpulmonary gradient (TPG)—the difference between mean pulmonary artery and wedge pressures, was calculated. The relationship between PH profile and MACE (death, heart failure hospitalization) was assessed using survival analysis. CMR and RV parameters were correlated with MACE using Cox-Regression analysis. To evaluate the importance of parameters for predicting MACE, Random Forest algorithm for survival analysis were applied.

Results:
A total of 52 patients were included (age 69±9 years, 85% male, 60% transthyretin, and 40% light chain CA). PH was present in 50 (96%) patients. RHC was performed during biopsy in 44(85%) and for clinical indications in 8(15%) patients. Rates of no PH, pre-capillary PH, IPC-PH, and CPCPH were 5(10%), 3(6%), 29(55%) and 15(29%) respectively (Panel A). Hemodynamic PH profile did not correlate with death (p=0.98) or MACE (p=0.67) (Panel B). TPG (HR 0.88, CI 0.80-0.97), RV, (HR 0.95, CI 0.92-0.98), and LV ejection fraction (HR 0.95, CI 0.92-0.98) were significantly associated with MACE. In Random Forest analysis, LVEF, RVEF, and TPG were the most important predictors of MACE (Panel C).

Conclusions:
PH is highly prevalent in CA, even at the time of diagnosis. While IPC-PH was most common, CPCPH is not infrequent. TPG and RVEF are prognostic markers in this population.