bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10154: Efficacy of the New Calpain Inhibitor Npo2270 Compared with Enalapril in Mouse Models of Ventricular Remodeling and Heart Failure
Authors: Aluja David , Delgado-Tomas Sara , Llenas Jesus , Vazquez Enrique , INSERTE Javier
Published: March 2022

Introduction:
Ca
2+
-dependent proteases calpains contribute to adverse ventricular remodeling and heart failure (HF) in multiple experimental models. However, the efficacy of pharmacological calpain inhibition for treating HF in patients has not yet been tested mainly due to the limitations of available inhibitors.

Hypothesis::
To assess the effect of NPO-2270, a new ketoamide derivative with calpain inhibitory properties, against myocardial remodeling and HF, and compare its effectiveness with enalapril.

Methods:
C57BL6/J mice were subjected to transverse aortic constriction (TAC) for 28 days or to coronary occlusion for 45 min followed by 21 of reperfusion (IR). NPO-2270 and enalapril were orally administered once a day at 10 mg/Kg/day, starting 7 days after TAC surgery or at the onset of reperfusion. Echocardiographic data, markers of hypertrophy, fibrosis, calpain activity and calpain substrates were measured at different time points.

Results:
TAC and IR increased calpain expression and activity. Chronic oral administration of NPO-2270 and enalapril prevented progression of hypertrophy and interstitial fibrosis induced by TAC, and reduced scar area by 40% in mice subjected to IR with no significant differences between treatments. However, NPO-2270 attenuated myocardial dysfunction to a greater extent than enalapril in both experimental models (27% of EF reduction in the control group, 6% in NPO-2270 group and 16% in the enalapril group subjected to TAC, P=0.024 between NPO-2270 and enalapril groups; and 11.9% in the control group, 1.8% in NPO-2270 group and 8.8% in the enalapril group subjected to IR, P=0.160 between NPO-2270 and enalapril groups). These results correlated with better preservation of cell adhesion complex in the group treated with NPO-2270.

Conclusions:
Our data demonstrate that the calpain inhibitor NPO-2270 prevents the progression of hypertrophy and fibrosis with similar efficacy to enalapril but ameliorates cardiac dysfunction more effectively in two clinically relevant experimental models of HF. This study provides compelling evidence that the new calpain inhibitor NPO-2270 is an attractive candidate to determine the potential of calpain inhibition as a strategy for treating HF in patients.
Abstract 10155: The Atypical Presentation and Clinical Outcomes of Non-ST-Segment Elevation Acute Coronary Syndromes in Chronic Kidney Disease Patients
Authors: Kotruchin Praew , Tharawadee Kodchakorn , Tangpaisarn Thanat , phingoen pariwat
Published: March 2022

Introduction:
The atypical presentation of acute coronary syndromes (ACS) was a risk factor of unfavorable outcomes. It is not uncommon for chronic kidney disease (CKD) patients with ACS to present atypically.

Hypothesis:
We hypothesized that the atypical presentation of non-ST-segment elevation ACS (NSTE-ACS) in CKD patients might associate with poor clinical outcomes.

Methods:
This was a retrospective cohort study in Srinagarind hospital, Thailand, from 2014 to 2017. The CKD patients with NSTE-ACS were enrolled. Clinical data including presenting symptoms, laboratory results, treatments, and outcomes were collected from an electronic database. The atypical presentation was defined as nausea and/or vomiting, dyspepsia, confusion, dyspnea, or no chest pain. The outcome was a composite of all-cause mortality, the over 30-day length of stay, and recurrent ACS underwent PCI or CABG.

Results:
There were 147 patients enrolled, of those, 77 (52.3%) presented with atypical symptoms. The atypical presentation group had a faster heart rate (HR) compared with those who presented with typical symptoms (87 vs. 78 beats per minute, P=0.005), however, both groups had comparable age, sex, and echocardiographic parameters. The determinant of the atypical presentation was HR (Odds ratio (OR) 1.03, 95%CI: 1.01-1.05). Atypical symptoms and diabetes mellitus were associated with the outcome, adjusted OR 2.62, 95%CI: 1.21-5.67, and adjusted OR 3.54, 95%CI: 1.56-8.03, respectively.

Conclusions:
ACS should be one of the differential diagnoses in the CKD patients who presented with nausea and/or vomiting, dyspepsia, confusion, dyspnea, or no chest pain. Considered that the atypical presentation was associated with poorer outcomes.
Abstract 10160: Population Eligible for PCSK9i in Spain: A Real-World Analysis
Authors: Cosin Sales Juan , Sidelnikov Eduard , Villamayor Galli Santiago , Fernandez Delgado Miriam , Torres Romero Elena , Zamora Alberto
Published: March 2022

Background:
Cardiovascular (CV) diseases are the leading cause of mortality globally. Reducing low-density lipoprotein cholesterol (LDL-C) is a proven strategy to decrease risk of acute CV events. The study aimed to estimate a PCSK9i-eligible population in Spain.

Methods:
We conducted a retrospective cohort study based on real-world data from the IQVIA Spanish Electronic Medical Records primary care database. Adult (≥18 y.o.) patients registered in the database between 2014 and 2020, diagnosed with myocardial infarction (MI), unstable angina (UA), ischemic stroke (IS), transient ischemic attack (TIA) or peripheral artery disease (PAD) and with at least 1 measurement of LDL-C or total cholesterol were included in the study and followed up for up to 12 months from the initial diagnosis.

Results:
The study included 9,516 patients; mean (SD) age was 67.7 (12.5) years, 63.9% were male and mean LDL-C was 117.3 (38.8) mg/dL. In the study population 28.5% of patients suffered an MI as most severe event during the study period, 10.0% had UA, 18.7% were diagnosed with IS, 13.6% with TIA, and 29.3% with PAD. At the time of last available LDL-C assessment (≥3 months after diagnosis), 64.4% of patients were on lipid lowering therapy (LLT). Of those, 45.4% were on high-intensity LLT (high-intensity statins with/without ezetimibe or PCSK9 inhibitors), 46.9% on moderate-intensity statins, and 7.7% on low-Intensity LLT (low-intensity statins, ezetimibe alone or non-statin LLT). Overall, 12.9% of treated patients achieved LDL-C levels <55 mg/dL; this proportion was the highest among those on high-intensity statins and any statin combined with ezetimibe (63.2%), followed by patients on moderate intensity statins (32.6%) and those on low-intensity LLTs (3.1%). A total of 17.1% of patients receiving optimized LLT had an LDL-C>100 mg/dL (LDL-C reimbursement threshold for PCSK9i in Spain).

Conclusions:
More than 85% of patients at very-high risk of cardiovascular events in our cohort do not achieve LDL-C <55 mg/dL recommended by 2019 ESC/EAS guidelines for management of dyslipidemia. More than 17% of the patients have LDL-C >100 mg/dL despite being treated with maximally tolerated LLT and, therefore, would be eligible for using PCSK9i within Spanish reimbursement criteria.
Abstract 10162: NT-proBNP is Associated with Stroke, Heart Failure Hospitalizations, and Death in Patients with Atrial Fibrillation Without Oral Anticoagulation Regardless of Heart Rhythm
Authors: Tomasdottir Maria , Hijazi Ziad , Lindback Johan , Benz Alexander , Connolly Stuart J , Eikelboom John W , Siegbahn Agneta G , Wallentin Lars C , Oldgren Jonas
Published: March 2022

Background:
NT-proBNP is elevated in patients with a diagnosis of atrial fibrillation (AF) and associated with risk of stroke and other outcomes. The associations have mainly been studied in patients on oral anticoagulation and not considering if samples were obtained during AF or sinus rhythm. We investigated the association of NT-proBNP with heart rhythm and cardiovascular (CV) events in patients with AF without oral anticoagulation.

Methods:
Plasma samples were obtained at baseline in 3184 patients with diagnosis of AF (2142 in AF rhythm at blood sampling) receiving aspirin in two multicenter randomized clinical trials with median follow-up 1.2 years (AVERROES) and 3.8 years (ACTIVE A), respectively. NT-proBNP was analyzed using Elecsys electrochemiluminescence immunoassay. Association of NT-proBNP with clinical variables was assessed with multivariable linear regression models. Association with outcomes were estimated with Cox-regression models adjusting for clinical variables.

Results:
Median age was 71 years, 57.8% were men, and median NT-proBNP 713 ng/L (25
th
-75
th
percentiles, 282-1388 ng/L). Variables contributing to NT-proBNP level were, in reducing order: AF rhythm (ratio of geometric means 2.9), age, creatinine, and prior heart

failure. Levels of NT-proBNP were significantly associated with ischemic stroke (HR 3
rd
vs 1
st
quartile 2.1, 95%CI 1.5-3.0), heart failure hospitalizations (HR 2.2, 95%CI 1.6-2.9), and CV death (HR 2.4, 95% CI 1.8-3.3), all p<0.001, without significant interaction with AF rhythm. Figure depicts NT-proBNP distribution by rhythm and association with ischemic stroke.

Conclusion:
In patients with a diagnosis AF, plasma levels of NT-proBNP are three times higher during AF rhythm compared with sinus rhythm. Higher levels of NT-proBNP are independently associated with ischemic stroke, heart failure hospitalizations, and CV death in AF patients without oral anticoagulation treatment, irrespective of heart rhythm.
Abstract 10165: The Correlation of Age and Extension Length in Debakey Type I Aortic Dissection: Are Septuagenarians at a Lower Risk?
Authors: Merkle-Storms Julia , Wahlers Thorsten , Feisst Manuel , Poeling Jochen , Rylski Bartosz , Dohle Daniel S , Hagl Christian , Krueger Tobias , Brickwedel Jens , Holubec Tomas , Etz Christian D , Noack Thilo , ARIF RAWA , Boening Andreas , Luehr Maximilian
Published: March 2022

Introduction:
Elderly patients have been suggested to be more prone to acute aortic dissection due to a higher incidence of age-related atherosclerosis and stiffness of the thoracic aorta.

Hypothesis:
Younger patients suffer more extensive DeBakey type I dissections due to aortic wall integrity, potentially allowing unhindered extension. The study's aim was to correlate age and dissection extension length in a large contemporary multi-center cohort.

Methods:
The perioperative data of 3385 patients with acute aortic dissection were retrospectively analyzed with regard to postoperative outcome and dissection extent. DeBakey type I aortic dissections (n=2510) were identified and divided into two groups: <70 years (n=1741) and >70 years (n=769). Patients with DeBakey type II and connective tissue disease were excluded (n=875).

Results:
Septuagenarians (>70 yrs) had a higher incidence of atherosclerosis (32.0% vs. 18.9%; p<0.001) and showed significantly more often a limitation of dissection extension until the aortic arch level (40.9% vs. 29.2%; p<0.001). In younger patients, aortic dissections involved the supraaortic vessels more often (52.0% vs. 40.1%; p<0.001) and extended significantly further downstream the aorta: descending aorta (68.5% vs. 57.1%; p<0.001), abdominal aorta (54.7% vs. 42.0%; p<0.001) and iliac bifurcation (36.6% vs. 26.0%; p<0.001) (
Fig.1
). Clinically, younger patients presented with significantly higher incidences of preoperative cerebral (p=0.002), spinal (p=0.003), visceral (p=0.002) and peripheral (p<0.001) malperfusion. In-hospital mortality rates in patients <70 yrs and >70 yrs were 18.9% and 22.2% (p=0.067), respectively.

Conclusions:
Extensive DeBakey type I aortic dissection is less frequent in septuagenarians. Conversely, younger patients suffer significantly more often from preoperative organ malperfusion and associated complications. Postoperative mortality remains high irrespective of age groups.
Abstract 10166: Incidence and Outcomes of Heparin-Induced Thrombocytopenia Among Patients Undergoing Left Ventricular Assist Device Implantation
Authors: Ajibawo Temitope , Okunade Adeniyi , Chauhan Priyank , Okunowo Oluwatimilehin
Published: March 2022

Background and Objectives:
Heparin-induced thrombocytopenia (HIT) increases the risk of thromboembolic and bleeding events. HIT is also a well-known complication in patients undergoing left ventricular assist device (LVAD) implantation, although most studies are limited to case reports/series and single-center experiences. The main objective of this study is to examine the incidence and impact of HIT on outcomes in LVAD implants using a nationwide database.

Methods:
Using the National Inpatient Sample database (2007-2014), we identified patients ≥ 18 years that underwent LVAD implants using ICD-9 codes. LVAD implants were stratified by the presence of HIT. The primary and secondary endpoints were the impact of HIT on mortality and other outcomes respectively.

Results:
Out of the 15,083 LVAD implantations, HIT occurred in 331 (2.2%). Although not statistically significant, the annual incidence of HIT rose from 1.3% in 2009, peaked at 3.3% in 2012 and decreased to 2.0% (ptrend = 0.6171). In-hospital mortality (OR 2.21, 95% CI 1.30-3.74, p = 0.0034) and post-operative DVT/PE (OR 2.45, 95% CI 1.09-5.51, p = 0.0303) were significantly associated with HIT. Our analysis did not show any differences in the incidence of vascular complications, post-op stroke/TIA, hemorrhage requiring transfusion and acute kidney injury between HIT and non-HIT group. The HIT group stayed longer in the hospital (30 vs 27 days, p < 0.0001) and incurred higher total hospital charges ($695,834 vs. $640,089 p < 0.0001).

Conclusion:
Among patients undergoing LVAD implants, HIT was associated with higher risk of in-hospital mortality, post-op DVT/PE, higher hospital charges and longer hospital stay.
Abstract 10168: Association Between the Grade of Cytokine Release Syndrome and Cardiac Dysfunction After Chimeric Antigen Receptor T Cell Therapy for Diffuse Large B Cell Lymphoma Patients
Authors: Sunayama Isamu , Orihara Yoshiyuki , Min Kyung-duk , Yoshihara Satoshi , Yoshihara Kyoko , Matsumoto Yuki , Nishimura Koichi , Horimatsu Tetsuo , Naito Yoshiro , Goda Akiko , Tamaki Hiroya , Higasa Satoshi , Asakura Masanori , Ishihara Masaharu
Published: March 2022

Introduction:
As Chimeric Antigen Receptor T cell (CAR-T) therapy gains its clinical advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it often accompanies cardiac dysfunction. Previous retrospective studies indicated the involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy, but their association is not fully investigated. Therefore, we designed a prospective study to clarify the association between the grade of CRS and cardiac dysfunction in the DLBCL patients after CAR-T therapy.

Methods:
In this prospective study, 14 DLBCL patients who underwent CAR-T therapy from July 2020 to May 2021 were enrolled. Before and after CAR-T therapy, we collected the levels of troponin T (TnT) as a marker for myocardial damage, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) as markers for systolic function, and E/e’ and left atrial volume index (LAVI) as markers for diastolic function. We classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely the low-CRS Group (CRS<3) and the high-CRS Group (CRS≧3). The markers for cardiac injury and dysfunction were further analyzed in both groups.

Results:
Average age was 56.4 years and 7 patients (50%) were female. The number of patients in the low-CRS and high-CRS Group were 11 and 3, respectively. Before CAR-T therapy, there were no differences in cardiac function between the two groups. From the hyper-early phase of CAR-T therapy, the increase of TnT, E/e’ and LAVI from the baseline were significantly larger in the high-CRS Group compared to the low-CRS Group (P=0.023, 0.039, and 0.024, respectively). Subsequently, the decrease of GLS from the baseline became significantly larger in the high-CRS Group compared to the low-CRS Group (P=0.049). These results indicated that cardiac dysfunction after CAR-T therapy occurred in the order of myocardial damage, diastolic dysfunction, and systolic dysfunction.

Conclusion:
We for the first time demonstrated the association between high-grade CRS and cardiac dysfunction after CAR-T therapy through a prospective study.
Abstract 10180: Clinical and Subclinical Rheumatic Heart Disease Among Adults in the Amazon Basin: A Cross-Sectional Study
Authors: Wegener Alma , Holm Anna Engell , Gomes L. , Lima K. , Matos L. , Vieira I. , Kaagaard Molly D , Souza R. , Marinho C , B-S T , ms o , Brainin Philip
Published: March 2022

Introduction:
Rheumatic heart disease (RHD) remains a significant cause of morbidity and mortality in middle- and low-income countries. However, the prevalence of RHD is often underestimated in resource limited areas due to lack of proper screening programs.

Purpose:
We aimed to determine the prevalence of clinical and subclinical RHD among adults in the Northwestern part of the Amazon Basin, Brazil. In addition, we evaluated the diagnostic yield of a history of self-reported rheumatic fever (RF) and cardiac auscultation

Methods:
We included a probability sample of adults from the general population in the Amazon Basin. Participants underwent questionnaire on medical history, cardiac auscultation and echocardiography. Participants were assessed according to the 2012 World Heart Federation (WHF) Criteria for echocardiographic diagnosis of RHD (Figure A)

Results:
We included a total of 591 participants (mean age 41+/-15 years, 60% women, 5% <20 years old). 3% (n=19) had definite RHD (age 50 [IQR 29-70] years, 53% women) and <1% (n=2) had borderline RHD. The distribution of definite RHD according to the WHF Criteria 2012 was: A (n=8), B (n=3), C (n=0), D (n=8). Valve pathologies are displayed in Figure B. Among definite RHD cases, 16% (n=3) were considered clinical (prevalence ~1%) and 84% (n=16) were subclinical (prevalence ~3%). A self-reported history of RF had a sensitivity of 3% and a specificity of 92% (PPV 2%/ NPV 95%) to detect RHD, whereas cardiac auscultation had a sensitivity of 38% and a specificity of 80% (PPV 5%/ NPV 97%). When combining a self-reported history of RF with cardiac auscultation, this yielded a sensitivity of 3% and a specificity of 98% (PPV 10%/ NPV 96%)

Conclusions:
By applying the 2012 WHF Criteria, the prevalence of clinical and subclinical RHD in adults from the Northwestern part of the Amazon Basin was 1% and 3%, respectively. A combination of a self-reported history of RF and cardiac auscultation provided low sensitivity but high specificity for RHD.
Abstract 10181: The Effect of Immune Checkpoint Inhibitors for Cancer on Blood Pressure
Authors: Drobni Zsofia D , Mayrhofer Thomas , Zafar Amna , Raghu Vineet , Gilman Hannah K , Hartmann Sarah , Quinaglia Thiago , Karady Julia , Gongora Carlos , Zubiri Leyre , Maurovich-Horvat Pal , Reynolds Kerry , Neilan Tomas G
Published: March 2022

Introduction:
Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers and the use of ICIs has been associated with an increase in atherosclerotic cardiovascular disease (ASCVD) events. The mechanisms involved in the increase in ASCVD with ICIs are incompletely understood. These same immune checkpoints targeted for cancer also regulate vascular function, yet there are no data testing the effect of ICIs on blood pressure.

Hypothesis:
Based on basic data on the role of these immune checkpoints in vascular function, we hypothesize that the use of ICIs would increase systolic and diastolic blood pressure.

Methods:
This was a single academic medical center study of 8,724 patients treated with an ICI. The primary analysis evaluated whether exposure to ICIs was associated with changes in blood pressure using repeated measures multivariate mixed linear regression models. The secondary analysis evaluated the effect of changes in blood pressure on all cause mortality using Cox proportional hazard models.

Results:
Of the 8,724 patients, 4,812 (55.2%) had a diagnosis of hypertension at ICI start. The average blood pressure at ICI start was 128.3±18.1/72.5±10.1mmHg. Among the entire cohort, there was a decrease of 2.9 mmHg in systolic blood pressure (95% CI: 2.70-3.02) after starting an ICI, and a drop of 1.6 mmHg (95% CI: 1.52-1.70) in diastolic blood pressure (adjusted, p<0.001 for both) (Figure 1). The effect of an ICI on blood pressure was independent of the development of any toxicity associated with an ICI. Patients who had an increase of ≥20 mmHg in systolic blood pressure after starting ICI had a lower risk of all-cause death (HR 0.74, 95% CI: 0.63-0.86) compared to patients with no or less than ≥20 mmHg increase.

Conclusions:
Among a large cohort of patients, ICI therapy is associated with a drop in systolic and diastolic blood pressure. However, patients who had an increase of at least ≥20 mmHg in systolic blood pressure had lower risk of all-cause death.
Abstract 10185: Interaction Between Sex and Left Ventricular Reverse Remodeling and Its Association with Outcome After Transcatheter Aortic Valve Implantation
Authors: Kuneman Jurrien H , Butcher Steele , Stassen Jan , Singh Gurpreet , Milhorini Pio Stephan , Hirasawa Kensuke , van der Kley Frank , Ajmone Marsan Nina A , Knuuti Juhani , Bax Jeroen J , Delgado Victoria
Published: March 2022

Introduction:
Women with severe aortic valve stenosis (AS) have better long-term prognosis after transcatheter aortic valve implantation (TAVI) compared to men. Whether this is caused by sex-related differences in left ventricular (LV) reverse remodeling after TAVI is unknown.

Purpose:
To examine the interaction between sex and LV reverse remodeling with outcome after TAVI.

Methods:
Patients with severe AS who had undergone transfemoral TAVI between 2007 and 2018 were selected. LV dimensions, volumes and ejection fraction (LVEF) were assessed by transthoracic echocardiography at baseline before TAVI, and at 6 and 12 months after TAVI. LV reverse remodeling was defined as %LV mass index (LVMi) reduction from baseline. The primary outcome was all-cause mortality.

Results:
A total of 459 patients (80±8 years; 52% male) were included. Before TAVI, indexed LV end-diastolic and end-systolic volume as well as LVMi were smaller in women versus men. At 6 and 12 months follow-up, both sexes showed significant reductions in LV volumes and LVMi accompanied by improvement in LVEF, without significant differences between the sexes over time (p for interaction=0.51, p=0.43, p=0.44 and p=0.30, respectively). During a median follow-up of 2.8 [IQR 1.9-4.3] years, 181 (39%) patients died. Women showed better outcome compared to men (log-rank p=0.024). In addition, male sex was independently associated with all-cause mortality in multivariable Cox regression (HR 1.423, 95% CI: 1.039-1.951, p=0.028). No association was observed between the interaction of %LVMi reduction and sex with outcome (p=0.64).

Conclusions:
Patients with severe AS had significant improvement in LVEF, reduction in LV volumes and LVMi at 6 and 12 months after TAVI, without significant differences between sexes over time. Women showed better survival after TAVI as compared to men despite being treated at older age. The interaction between %LVMi reduction and sex was not associated with survival.
Abstract 10187: Renin-Angiotensin-Aldosterone System Inhibitors and Overall Survival in Cancer Patients Treated with Immune Checkpoint Inhibitors
Authors: Drobni Zsofia D , Michielin Olivier , Quinaglia Thiago , Zlotoff Daniel , Zubiri Leyre , Merkely Béla , Sullivan Ryan , Reynolds Kerry , Pittet Mikael , Jain Rakesh , Neilan Tomas
Published: March 2022

Introduction:
Preclinical studies indicate that the concurrent use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) may improve outcomes in broad groups of patients with cancer. There are limited data on the association between inhibitors of RAAS and outcomes among patients treated with immune checkpoint inhibitors (ICI).

Hypothesis:
RAAS inhibitors improve overall survival in patients treated with ICI.

Methods:
We performed a retrospective study of all patients treated with an ICI in a single academic network. Of 10,903 patients; 5,910 were on any anti-hypertensive medication. Of those on anti-hypertensive therapy, 3,426 were prescribed any RAAS inhibitor during ICI treatment and 2,484 were prescribed other anti-hypertensive medications. The primary outcome was overall survival in the entire cohort and in sub-groups by type of cancer.

Results:
Thoracic cancer (34%) and melanoma (16%) were the most common types of cancer and programmed cell death protein 1 inhibitor therapy was the most prescribed (76%). Those prescribed a RAAS inhibitor were older, more likely male and had more cardiovascular risk factors. In a Cox proportional hazard model, the concurrent use of RAAS inhibitors was associated with better overall survival (Figure). Among the different cancer types, there was a trend toward better overall survival among patients with gastrointestinal (Hazard Ratio (HR):0.82, [95% Confidence Interval (CI): 0.67-1.01], P=0.057) and genitourinary cancer (HR:0.81, [95% CI: 0.64-1.01], P=0.067).

Conclusions:
In this large retrospective study, patients who were concomitantly prescribed a RAAS inhibitor during ICI therapy had a better overall survival. The benefit of RAAS inhibitors was primarily noted among patients with gastrointestinal and genitourinary cancers. Prospective randomized trials are warranted to further evaluate and specify the benefit of RAAS inhibitors in cancer patients who receive ICI therapy.
Abstract 10191: Dapagliflozin versus Empagliflozin for Improving Outcomes of Non-Diabetic Patients with Heart Failure and Reduced Ejection Fraction
Authors: Arbel Ronen , Azuri Joseph , Aboalhasan Enis , Hammerman Ariel
Published: March 2022

Introduction:
Patients with HF and reduced ejection fraction (HFrEF) are at high risk for CV mortality and HF-related hospitalizations (HHF). The Sodium-Glucose Transport protein 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin improve the outcomes of non-diabetic patients with HFrEF. We aimed to compare their value for money for this indication.

Hypothesis:
Empagliflozin and dapagliflozin have comparable value for money for improving the HF outcomes of non-diabetic patients with HFrEF.

Methods:
SGLT2i data was extracted from published results of empagliflozin and dapagliflozin in the subgroups of patients without diabetes. The primary clinical outcome measure was a composite of HHF or CV mortality events. The economic measure was the cost needed to treat (CNT) to prevent one event, calculated by multiplying the one-year number needed to treat (NNT) to prevent one event by the annual cost of each therapy. Drug costs were based on the 2021 US National Average Drug Acquisition Cost prices. Secondary outcomes were the CNT to prevent one event of HHF and CV mortality as separate clinical outcomes. Sensitivity analysis was performed to mitigate differences between the trial’s populations

Results:
Treatment with empagliflozin in EMPEROR-REDUCED has resulted in an NNT of 29 (95% CI: 18-212) compared to 32 (95% CI: 21-72) with dapagliflozin in DAPA-HF. Accordingly the CNT to prevent one event of CVM or HHF was $139,115 (95% CI: $86,347-$1,016,976) and $144,751 (95% CI: $94,993-$325,690), respectively. The sensitivity analysis confirmed the primary results, but the CNT to prevent CV mortality is significantly lower with dapagliflozin (Fig. 1)

Conclusions:
Empagliflozin and dapagliflozin have comparable value for money for improving HF outcomes of non-diabetic patients with HFrEF, with an advantage for dapagliflozin in CV mortality.
Abstract 10192: Circular RNA Formation in the Failing Heart is Enhanced by the Reduction of Adenosine-to-Inosine RNA Editing
Authors: Kokot Karoline Elizabeth , Kneuer Jasmin M , John David , Moebius-Winkler Maximilian N , Müller Marion , Andritschke Michael , Gaul Susanne , Sheikh Bilal N , Haas Jan , Thiele Holger , Leuschner Florian , Dimmeler Stefanie , Meder Benjamin , Laufs Ulrich , Boeckel Jes-Niels
Published: March 2022

Introduction:
Adenosine-to-Inosine (A-to-I) RNA editing is a post-transcriptional modification process regulating RNA stability and alternative splicing. A-to-I RNA editing is conducted by the enzymes ADAR1 and ADAR2 and mainly targets Alu elements, primate-specific elements which have been associated with the formation of circular RNA (circRNA). Although differential expression of circRNAs has been studied in heart failure (HF), the extent of A-to-I RNA editing and consequences in the human heart remain largely unknown.

Methods and Results:
We analyzed RNA editing in human heart samples of HF (n=20) patients and controls (n=10) using RNA sequencing. We found a reduction of A-to-I RNA editing in intronic Alu elements of protein-coding genes in HF patients compared to controls. The majority (96%) of regulated circRNAs were upregulated. The predicted back-splice sites (BSS) of 20 circRNAs were validated by qPCR. The circRNA candidates correlated with RNA editing (R=0.47, P=0.02). Among the upregulated circRNAs, we identified two circular transcripts (circAKAP13) derived from the AKAP13 gene, which showed reduced A-to-I RNA editing in HF (-70.7%, n=20). In HF, ADAR2 was reduced (-68.2%) and ADAR1 was increased (7.41±0.13 -fold) on protein level (n=3-6). The knockdown of ADAR1 did not alter circRNA levels, whereas the knockdown of ADAR2 led to significantly upregulated levels of circAKAP13 (1.88±0.42 -fold, n=6). Consistently, ADAR2 overexpression reduced circAKAP13 expression (-41%, n=3). Using two mini-genes containing exons 15-19 of the AKAP13 gene and flanking Alu elements, we found convergent Alu elements enhancing circAKAP13 expression.

Conclusion:
In conclusion, these data describe the A-to-I RNA editome in the human heart for the first time. Reduced A-to-I RNA editing in HF patients is associated with elevated circRNA levels. We propose a primate-specific splicing mechanism mediated by A-to-I RNA editing in the human heart. These findings contribute to a better mechanistic understanding of A-to-I RNA editing in cardiac diseases.
Abstract 10197: Cavin1, a Novel Actor in Drug Induced Long Qt
Authors: Al Sayed Zeina , Pereira Celine , Jouve Charlene , Hulot Jean S
Published: March 2022

Introduction:
Many drugs have been pulled from the market due to their undesirable effect in prolonging the QT interval by altering cardiac ion currents, notably I
Kr
generated by hERG. This cardiotoxic impact is however extremely variable between individuals and the mechanisms underlying this variability remain undiscovered. Previously, we identified a higher expression of CAVIN1, an essential protein for caveolae biogenesis, in cardiomyocytes (CM) derived from individuals with high susceptibility to develop sotalol-induced long QT.

Hypothesis:
CAVIN1 can modulate cardiomyocytes’ response to drugs.

Methods:
We used induced pluripotent stem cells-derived-CM (iCM) from 3 subjects with the highest sensitivity (HS) to sotalol (ie, those with the highest increase in QTc) and 3 others with the lowest sensitivity to sotalol (LS).

Results:
cardiac repolarization and I
Kr
were similar between HS-iCM and LS-iCM at baseline. However, HS-iCM displayed a significantly higher prolongation of the repolarization phase along with a decrease in I
Kr
in response to sotalol and other drugs targeting hERG (E4031, vandetanib, and clarithromycin). CAVIN1 mRNA and protein levels were increased by 2-fold in the HS-iCM. Overexpressing CAVIN1 in the LS-iCM using adenovirus induced higher sensitivity to sotalol and the other hERG blockers. In contrast, CAVIN1 knockdown using siRNA in the HS-iCM switched their phenotype to a lower sensitivity to hERG blockers. We observed that CAVIN1 overexpression in LS-iCM and HEK cells changed hERG distribution within cells with accumulation at the membrane. We applied Methyl-β-cyclodextrin, a detergent that removes caveolae from membranes, and found that caveolae depletion induced prolonged repolarization associated with a decrease in CAVIN1 and hERG sarcolemmal expression, and their accumulation in the cytoskeleton. In contrast with the LS-iCM, sotalol application in the HS-iCM promoted hERG internalization into the cytoskeleton.

Conclusions:
We identified CAVIN1 as a novel modulator of cardiac repolarization in response to drug by promoting hERG internalization. This represents a novel mechanism sustaining the inter-individual variability in response to drugs.
Abstract 10199: Establishing Human Ipsc-Derived Vascular Organoids as Angiogenesis Model
Authors: Trillhaase Anja , Aherrahrou Zouhair , Erdmann Jeanette
Published: March 2022

Recent large-scale GWA meta-analyses identified more than 240 risk loci associated with coronary artery disease (CAD) on a genome-wide significance level. Pathway analyses confirmed established pathomechanisms contributing to the progression of CAD like lipid metabolism, inflammation, extracellular matrix remodelling, or neoangiogenesis. Human induced pluripotent stem cells (iPSCs) offer a great source to derive 3D models, so-called organoids, allowing a more physiological environment to be analyzed
in vitro
. We aim to establish vascular organoids from iPSCs as 3D model of angiogenesis to investigate the role of CAD- and angiogenesis-associated risk genes like
ADAMTS7
,
ARNTL
, and
TBX20
.Four iPSC lines (UCSD18i-3-6, female, healthy; WC028i-5807-6, female, healthy; UCSD167i-99-1, female, healthy; UCSD179i-27-1, male, healthy; all from skin fibroblasts) will be differentiated into vascular organoids following the protocol published by Wimmer et al (2019). The first iPSC lines were differentiated to estimate the optimal seeding density for each cell line, and organoids were characterized. During embedding of aggregates for vascular sprouting organoids will be used for angiogenesis assay, and sprout length and number will be analysed. Different inhibitors and stimulators of angiogenesis can easily be applied proving that vascular organoids can be used as angiogenesis model. Using siRNA we will then knock-down (KD) above-mentioned risk genes, assessing their effect on angiogenesis. Additionally, cells will be edited using CRISPR/Cas to knockout the same risk genes.The first organoids showed expression of pericyte (PC) and endothelial cell (EC) markers on RNA level, while smooth muscle cell markers were not expressed. These results were confirmed in immunofluorescence stainings in whole organoids. Additionally, we performed cryosections which we also stained with immunofluorescence, showing an even distribution of cells. Staining of the cryosections further confirmed expression of PC- and EC markers. In conclusion, we successfully established iPSC-derived vascular organoids from iPSCs. We have now a 3D cell model in our hand to study GWAS candidate genes and their role in angiogenesis in the context of CAD.
Abstract 10202: Ethnic/Racial Differences in Comorbidities and Outcome Among Patients with Amyloidosis: An Analysis of the National Inpatient Sample Database
Authors: Ream Sarah , Ma Jennifer , Rodriguez Tayana , Sarabia-Gonzalez Alejandro , Alvarado Luis , Dwivedi Alok , Mukherjee Debabrata
Published: March 2022

Background:
Amyloidosis is due to an abnormal extracellular deposition of insoluble fibrils in tissues. Prior studies have evaluated age and gender differences with amyloidosis, but there are no studies on racial/ethnic differences in risk factors and outcomes. We evaluate prevalence, characteristics, and outcomes in patients with amyloidosis across ethnic/racial groups.

Methods:
We performed a retrospective study utilizing the Nationwide Inpatient Sample (NIS) database from 2015 to 2018 using ICD-10 codes. We assessed demographics including age, race, gender and comorbidities including diabetes, hypertension, heart failure, pulmonary disease, coronary artery disease and renal failure according to ethnic/racial groups. Primary outcome was mortality. Unadjusted and adjusted relative risks (RR) with 95% confidence interval (CI) were calculated using survey weighted regression analysis.

Results:
Of the total population, amyloidosis prevalence was 0.17% (N=34,894). Blacks (RR 1.7, 95% CI 1.65-1.75, P <.0001) and Hispanics (RR 1.27, 95% CI 1.22-1.33, P <.0001) were more likely to be admitted to the hospital with amyloidosis compared to Whites. However, mortality was significantly higher among Whites while renal failure was higher in Blacks and Hispanics (P <.0001).

Conclusion:
Our study suggests significant ethnic/racial differences in baseline characteristics and outcomes for hospitalized patients with amyloidosis. Mortality was significantly higher in White patients as compared to Blacks and Hispanics although Whites were significantly older and had more comorbidities. Additional studies are indicated to better understand differences in outcomes across ethnic/racial groups and the higher mortality in white individuals.
Abstract 10205: Usefulness of a Systemic Inflammation-Nutrition Index for the Prediction of Post Discharge Prognosis in Patients with Heart Failure with Preserved Ejection Fraction: Insights from Pursuit-hfpef Registry
Authors: Sakamoto Daisuke , Seo Masahiro , Yamada Takahisa , Tamaki Shunsuke , Yano Masamichi , Hayashi Takaharu , Nakagawa Akito , Nakagawa Yusuke , YASUMURA YOSHIO , Hikoso Shungo , Sotomi Yohei , Sakata Yasushi ,   the OCVC-Heart Failure Investigator
Published: March 2022

Background:
Malnutrition and inflammation are associated with poor outcomes with heart failure (HF). It has been reported that Advanced Lung cancer Inflammation index (ALI), calculated by body mass index х serum albumin level / neutrophil to lymphocyte ratio (NLR) can be used for the prognosis assessment of various malignancies. In addition, it has been reported to be useful as a prognostic factor in HF patients. Then, we sought to clarify the prognostic value of ALI in patients with HF with preserved ejection fraction (HFpEF).

Methods and Results:
Patients’ data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study, which is a prospective multicenter observational registry for ADHF-HFpEF in Osaka. Laboratory data and body weight measurements were performed just before discharge. We analyzed 821 patients (mean age: 81 years old, male: 45%) after exclusion of patients on dialysis, in-hospital death, missing follow-up data, or missing data to calculate ALI. The primary endpoint of the present study was all-cause death (ACD). During a mean follow-up period of 1.8±1.0 years, 169 patients died. In multivariate Cox analysis, ALI was significantly associated with ACD independently of age, serum sodium level, hemoglobin level, and serum NT-proBNP level after adjustment for sex, NYHA functional class, systolic blood pressure, serum creatinine level, serum CRP level, past medical history of AF and LVEF. By ROC curve analysis, AUC of ALI was significantly greater than that of NLR. Kaplan-Meier curve analysis revealed that patients with lowest ALI (24.16 ≥ ALI categorized by tertile) had higher risk of ACD than those with highest ALI (ALI > 40.10) (32% vs 13%, adjusted HR 2.93. 95%CI [2.01-4.38], p<0.0001).

Conclusion:
ALI, a systemic inflammation-nutrition index, might be useful for stratifying ADHF patients with HFpEF at risk for the total mortality.
Abstract 10206: First
in-vivo
Evidence of Aureolysin (
aur
) Up-Regulation by
Staphylococcus Aureus
Causing Invasive Prosthetic Valve Endocarditis
Authors: Elgharably Haytham , Etiwy Muhammad , Tuohy Marion , Witten James , Procop Gary W , Sangwan Naseer , Shrestha Nabin , Claesen Jan , Cremer Paul , Navia Jose L , Svensson Lars G , Pettersson Gosta B
Published: March 2022

Background:
Staphylococcus aureus
prosthetic valve endocarditis (PVE) is resistant to antimicrobial therapy and commonly associated with tissue invasion, which necessitates complex high risk surgical intervention for cure.

Hypothesis:
S. aureus
virulence in infective endocarditis (IE) is dynamic and changes upon colonizing cardiac valves from blood stream.

Methods:
Six patients undergoing cardiac surgery for left-sided
S. aureus
IE, 3 native (NVE) and 3 PVE, were included in this study. Vegetation samples were collected during surgery as well as corresponding blood culture isolates during
S. aureus
bacteremia. Total RNA was extracted from all samples and underwent mRNA sequencing for transcriptomic analysis of
S. aureus
. Data was pooled into STAR aligner and gene expression related to virulence factors was compared between different groups (Deseq2; p-value < 0.05 for statistical significance).

Results:
In NVE vegetations,
S. aureus
showed an increased expression of genes associated with biofilm formation, cell division, and metabolic activity, when compared to blood culture isolates (e.g.
rsmA
,
agrB
,
dnaK
,
clpB
,
ezrA
,
fusA
,
ftsZ
,
adh
,
pstS
,
qoxA
).
S. aureus
isolated from blood cultures had significantly higher expression of
clfA
(encoding for clumping factor A) compared to cardiac vegetations. Interestingly, in PVE vegetations,
S. aureus
had a significant higher expression of
aur
(encoding for
metalloprotease
aureolysin) compared to corresponding blood culture isolates or NVE vegetations. Aureolysin is an important virulence factor responsible for immune evasion and toxin production.

Conclusions:
In clinical IE,
S. aureus
up-regulates genes responsible for biofilm formation when attached to cardiac valves. Planktonic
S. aureus
cells in the blood stream express
clfA
, which could bind to fibrinogen to clump within platelet network to form vegetations. On prosthetic valves,
S. aureus
expresses aureolysin, which could function to evade the host immune response and promote destruction of cardiac tissues. These novel
in-vivo
findings provide explanations for
S. aureus
IE pathophysiology that warrant further investigation.
Abstract 10211: Longitudinal Changes in Clinical and Imaging Variables During Withdrawal of Heart Failure Therapy in Patients with Recovered Dilated Cardiomyopathy: An Analysis from TRED-HF
Authors: Halliday Brian P , Owen Ruth , Gregson John , Vazir Ali , Lota Amrit S , Khalique Zohya , Cowie Martin R , Pennell Dudley , Cleland John , Prasad Sanjay K
Published: March 2022

Introduction:
In TRED-HF, 40% of patients with recovered dilated cardiomyopathy (DCM) relapsed during withdrawal of therapy. Non-invasive markers of relapse may be used to monitor patients who wish a trial of therapy withdrawal.

Purpose:
To profile the changes in clinical and imaging variables amongst patients with recovered DCM undergoing therapy withdrawal in TRED-HF.

Methods:
Patients with recovered DCM were randomised to phased withdrawal of therapy or to continue therapy for 6 months. After 6 months of continued therapy, those in the control arm underwent withdrawal of therapy in a crossover phase. Clinical variables were measured at each study visit and imaging variables were measured at baseline, 16 weeks and 6 months. Mean values and 95% CIs were calculated at each time point. Clinical variables were modelled using fractional polynomials.

Results:
Of 51 patients, 26 were assigned to continue therapy and 25 to withdraw therapy over the first 6 months. Of the former, 24 of 26 patients, withdrew therapy in the cross-over phase between 6-12 months. An increase in mean heart rate was noted within 4 weeks of beginning therapy withdrawal and was the earliest change observed. Heart rate and change in heart rate from baseline were closely associated with the occurrence of relapse in multivariable analysis. A rise in systolic and diastolic blood pressure was apparent by 8 weeks. A rise in mean log NT-pro-BNP was the latest change to occur and not observed until 6 months after starting therapy withdrawal. (
Figure 1 & Table 1)
. A rise in mean LV mass and LVEDV and a reduction in mean LVEF was seen by 16 weeks (
Figure 2 & Table 1)
.

Conclusion(s):
A rise in heart rate may be the earliest sign of relapse during withdrawal of medication. This is accompanied or closely followed by changes in LV structure and function, with changes in natriuretic peptide concentrations occurring later. This informs monitoring strategies in cases where it may be necessary to reduce heart failure therapy.
Abstract 10213: Acute Protein Kinase C Beta Inhibition Preserves Coronary Endothelial Function After Cardioplegic Hypoxia/Reoxygenation
Authors: Kant Shawn , Xing Hang , Liu Yuhong , Sellke Frank W , Feng Jun
Published: March 2022

Introduction:
Cardioplegic ischemia and reperfusion (CP-I/R) or CP-hypoxia and reoxygenation (CP-H/R) are associated with protein kinase C (PKC) overexpression/activation and coronary endothelial dysfunction.

Hypothesis:
This study aimed to determine whether acute inhibition of PKC could protect against CP-H/R-induced coronary endothelial dysfunction.

Methods:
Isolated small coronary arteries from mice (n = 6/group, male and female) were subjected to hyperkalemic, cardioplegic hypoxia (1 hour) and reoxygenation (1 hour) with Krebs buffer. The vessels undergoing CP-H/R were divided into 2 groups: those treated with the selective PKCβ inhibitor Ruboxistaurin (RBX, 50 nM, CP-H/R + RBX group) 5 minutes before and during CP-H/R, and those that received no treatment. Sham control vessels were continuously perfused with oxygenated Krebs buffer without CP-H/R and drug treatment. Vascular reactivity was measured by vessel myography. At the end of 1-hour re-oxygenation, all vessels were pretreated with endothelin-1; then, responses to the endothelium-dependent, NO-mediated vasodilator adenosine-diphosphate (ADP) and the endothelium-dependent/SK channel activator NS309 were examined.

Results:
CP-H/R caused a significant decrease in the coronary relaxation response to the endothelium-dependent, NO-mediated vasodilator ADP (10
-
4
M,
*
P
=0.006) and the SK channel activator NS309 (10
-5
M,
*
P
=0.0001) as compared with the Sham control group. Treatment with the selective PKCβ inhibitor RBX significantly increased the recovery of coronary relaxation responses to ADP (
#
P
= 0.031) and NS309 (

#

P
=0.004) compared with the untreated CP-H/R group (Figure).

Conclusion:
Acute inhibition of PKCβ significantly improved the recovery of coronary endothelial function after a period of CP-H/R injury in the mouse coronary microvasculature, suggesting that acute PKCβ inhibition may be a novel approach for protecting coronary endothelial function during CP-H/R.