bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14976: Proteomic Measures Linking Social Determinants of Health to Heart Failure Risk: The Atherosclerosis Risk in Communities Study
Authors: Ramonfaur Diego , Zierath Rani , Lamberson Victoria , Yang Yimin , Claggett Brian , Kucharska-Newton Anna , Walker Keenan A , Bhavsar Nrupen A , Chang Patricia , Diez Roux Ana V , Bey Ganga , Butler Kenneth R , Ndumele Chiadi E , Coresh Josef , Floyd James S , Odden Michelle C , Shah Amil M
Published: December 2023

Introduction:
Adverse social determinants of health (SDOH) are risk factors for heart failure (HF), and both disproportionately burden Black adults. The mechanisms linking SDOH to incident HF are unclear.

Methods:
Among 9910 HF-free participants in the community-based ARIC study with proteomic data (Somascan v4) at Visit 3 (V3; 1993-95), we performed race-stratified (Black and non-Black race) analyses of the association of 4955 plasma proteins with SDOH and incident HF. We derived a SDOH factor based on income, education level, and neighborhood area deprivation index using exploratory factor analysis. We evaluated cross-sectional associations of the SDOH factor with proteins using age- and gender- adjusted linear regression at Bonferroni significance. The association of SDOH-associated proteins with incident HF during 10 years post-V3 was assessed using Cox PH regression further adjusting for cardiovascular co-morbidities, using an FDR <0.05. Mendelian randomization analysis assessed for a possible causal effect on HF among candidate proteins common to both race groups.

Results:
Of 9910 participants, 1981 reported Black race (age 59±6 years; 60% female) and 7929 non-Black race (60±6; 52% female). The SDOH factor was associated with incident HF in both race strata (adjusted HR 1.29 [95% CI 1.07-1.54] and 1.38 [1.24-1.53] respectively). Among Black participants, 80 proteins associated with the SDOH factor, 52 of which associated with incident HF. Among non-Black participants, 866 proteins associated with the SDOH factor, 188 of which associated with incident HF. Twenty-two proteins were associated with SDOH and HF in both race groups (Figure). Mendelian randomization supported a possible causal effect of C1QTNF1, an inflammation-associated adiponectin paralog, on HF.

Conclusions:
Large scale proteomics identifies proteins potentially linking SDOH to HF risk. C1QTNF1 associates with SDOH burden, has a possible causal effect on HF, and warrants further study.
Abstract 15008: Novel Sheathless Guiding Catheter Equipped With Peel-Off External Dilator for Percutaneous Coronary Intervention With Distal Radial Approach - A Multicenter Study
Authors: Yamada Takeshi , Izumikawa Takuya , Takahashi Akihiko , Taniguchi Norimasa , Nakajima Shunsuke , Hata Tetsuya
Published: December 2023

Objectives:
Hyperion Sheathless guiding catheter (Asahi Intecc) is a novel guiding system for percutaneous coronary intervention (PCI) which is equipped with peel-off type outer dilator to facilitate smooth insertion of catheter tip. The aim of this study was to access feasibility and efficacy of this system for the patients who underwent PCI through distal radial artery.

Methods:
A total of 179 patients underwent PCI using a 6-Fr Hyperion sheathless guiding catheter in 2 hospitals. Of those, 168 patients including 27 patients with ST elevation myocardial infarction were treated with distal radial approach. Procedural success, bleeding complication and radial occlusion examined using Doppler ultrasound at discharge was accessed.

Results:
Mean age of the patients was 72.1 +/- 11.3 years and 114 patients were male. Procedural success was 100 % with no patient requiring conversion to conventional radial access. Doppler ultrasound examination of the distal radial artery at 1-day follow-up was available in all patients, with 2 patients (1.2%) was found to have radial artery occlusion. One patient presented forearm hematoma equivalent to EASY hematoma classification I and 4 patients showed dorsum hematoma.

Conclusions:
The current study illustrated that the use of the Hyperion Sheathless guiding catheter for distal radial PCI was feasible and associated with a low rate of procedure-related complications even in the patients with ST-elevation myocardial infarction.
Abstract 15021: Effect of Eplerenone on Cardiac Reverse Remodeling in Patients With Acute Heart Failure: A Sub-Analysis of the Earlier Randomized Double-Blind Trial
Authors: Ito Shin , Asakura Masanori , Kitakaze Masafumi
Published: December 2023

Background:
Activation of the renin-angiotensin-aldosterone system promotes left ventricular (LV) remodeling and dysfunction. In the EARLIER trial, we reported that the early initiation of eplerenone in patients with acute heart failure (AHF) reduced re-hospitalization for heart failure; however, its effect on cardiac reverse remodeling remains unclear.

Hypothesis:
Eplerenone attenuates LV remodeling in AHF patients with reduced ejection fraction (EF).

Methods:
In the EARLIER trial, hospitalized AHF patients with reduced EF (n = 300) were assigned randomly to either eplerenone (n = 149) or placebo (n = 151), once daily for 24 weeks. In this post-hoc analysis, absolute change in LVEF from baseline to 24 weeks was assessed by analysis of covariance adjusted for the baseline data. All participants treated with the study drug at least once were included in the analysis (eplerenone n=148, placebo n=149).

Results:
The absolute change in LVEF was not statistically different between the eplerenone and placebo groups (least square mean [LSM]difference: 2.81 ± 1.49, 95% CI: –1.25-5.21, P=0.06). The etiology of AHF consisted of acute myocardial infarction (AMI) (n=35) and non-AMI (n=265). LVEF was significantly improved by eplerenone in AMI patients (LSM difference: 8.04 ± 3.49, 95% CI: 0.90-15.18, P<0.05), but did not in non-AMI patients (LSM difference: 1.98 ± 1.64, 95% CI: –1.25-5.21, P=0.23). Eplerenone showed a 39% reduction in CV death and HF hospitalization in AHF patients with non-AMI, despite no significant difference compared with the placebo (Hazard ratio:0.61, 95% CI: 0.24-1.57, P=0.30).

Conclusions:
Treatment with a mineralocorticoid receptor antagonist of eplerenone for 24 weeks induced LV reverse remodeling in AHF patients with reduced EF due to AMI. Further extended observation is needed to investigate the effect of eplerenone on LV remodeling in AHF patients with reduced EF due to non-AMI.
Abstract 15030: Dapagliflozin Reduces Myocardial and Renal NF-kB Expression in Preclinical Models Exposed to Doxorubicin Through Myd-88 and NLRP3 Pathways: An Hystological Study
Authors: Maurea Nicola , Canale Maria L , Bisceglia Irma , Iovine Martina , Paccone Andrea , Merola Alessia , Gabrielli Domenico , Palma Giuseppe , Luciano Antonio , Bruzzese Francesca , Zito Matino Federica , Franco Renato , Quagliariello Vincenzo
Published: December 2023

Background:
Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and HFrEF, conditions that commonly coexist and are interrelated pathophysiologically.

Hypothesis:
We hypothesized that Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models

Methods:
Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100) , pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods.

Results:
DAPA improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-DAPA group compared to DOXO mice (p<0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in DAPA-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in DAPA-DOXO group vs DOXO (p<0.005). Hystology evaluation indicate reduction NF-kB expression in myocardial and renal tissue in DOXO-DAPA vs DOXO. Radial strain (RS) is 38.8% in DAPA-DOXO vs 14.1% in DOXO groups (P < 0.05); longitudinal strain (LS) is - 23.4 % in DAPA-DOXO vs - 10.5% in DOXO groups (P < 0.001)

Conclusion:
The overall picture of the study pushes the use of DAPA in prevention of cardiomyopathies induced by anthracyclines in cancer patients.
Abstract 15043: Dapagliflozin Reduces Systemic NLRP-3, IL-1 and PCSK9 Levels in Preclinical Models of Short-Term Doxorubicin Cardiotoxicity: New Evidences of SGLT2i Use in Cardioncology
Authors: Maurea Nicola , Canale Maria Laura , Bisceglia Irma , Palma Giuseppe , Luciano Antonio , Bruzzese Francesca , Iovine Martina , Merola Alessia , Paccone Andrea , Gabrielli Domenico , Maurea Fabrizio , Quagliariello Vincenzo
Published: December 2023

Background:
Anthracyclines are an effective and widely used chemotherapy agent in the treatment of multiple solid organ tumors and hematologic malignancies. The use of anthracyclines as a standard cancer therapy is limited by the potential for the development of cardiac dysfunction, arrhythmias, and clinical heart failure. In recent five years, it was demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), a lipid metabolism-related protein, is a key orchestrator of immune infiltration in myocardial and cancer tissues and could regulate cardiac fibrosis and inflammation. PCSK9 is a protein with key roles in hepatic low density lipoprotein (LDL) homeostasis. PCSK9 systemic levels are associated to HOMA score and high insulin levels. Dapagliflozin exerts systemic ant-inflammatory properties and cardioprotective effects in diabetic and non-diabetic patients.

Purpose:
We hypothesized that Dapagliflozin, administered during doxorubicin, could reduce PCSK9 systemic levels in preclinical models.

Methods:
Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). After treatments, plasma levels of PCSK9, IL-1β and CRP were analyzed through selective anti-mouse ELISA methods. Myocardial and liver expression of NLRP3-inflammasome and IL-1β were analyzed through ELISA method in tissue lysates after treatments.

Results:
DAPA associated to DOXO reduces significantly systemic levels of PCSK9 ( -37,5% vs DOXO group, p<0,001). IL-1β and CRP levels were also reduced ( -47,3 and - 28,5 %, respectively; p<0.05 for both). Myocardial and liver IL-1β and NLRP3 inflammasome expression were also reduced in DAPA/DOXO group vs DOXO and control, indicated beneficial metabolic and anti-inflammatory effects of SGLT2i.

Conclusion:
DAPA has been shown to reduce systemic levels of PCSK9 in preclinical models of short-term DOXO cardiotoxicity. To the best of our knowledge, this is the first evidence of SGLT-2/PCSK9 crass-talk in cardioncology therefore the overall picture of the study open a new window on the beneficial properties of DAPA against anthracyclines side effects.
Abstract 15046: Atrial Sarcomeric Dysfunction in
Ttntv
Mice Indicates a Causal Relationship Between Rare Variation in
TTN
and Early Onset Atrial Fibrillation in Patients
Authors: Kalstoe Silje Madeleine , Mattingsdal Morten , Rypdal Karoline B , Frisk Michael , Lundegaard Pia Rengtved , Tveit Arnljot , Olesen Morten S , Lunde Ida G , Christophersen Ingrid E
Published: December 2023

Background:
Atrial fibrillation (AF) is a common cardiac arrhythmia with a substantial genetic component. Rare variation in
TTN
and other sarcomeric genes have been associated with AF, in particular in early-onset disease.

Aim:
To describe the burden of rare, functional variants in a Norwegian early-onset AF population and to perform functional characterization in a
Ttn
truncating variant (
Ttntv
) mouse model.

Methods:
We performed whole-genome sequencing in 90 individuals with onset of AF before age 50 years and calculated the burden of rare, functional variation for all genes. Variant frequencies and gene burden from gnomAD 3.1.2 NFE were used as controls. The burden was defined as the sum of allele counts for rare (MAF<1%) and damaging variants (high and moderate impact) for each gene, and differences in burden was assessed using Fisher’s exact test. Functional characterization, including echocardiography, electron microscopy and mRNA expression analyses, was performed in atria from haploinsufficient
Ttntv
mice.

Results:
We identified an increased burden of rare, functional variation in 57 genes, including the sarcomeric genes
TTN
,
MYH6
and
OBSL1
, but also in the cell adhesion gene
DCHS2
, in individuals with early-onset AF.
Ttntv
mice had normal cardiac function assessed by echocardiography, but electron microscopy revealed structural remodeling of the atria, with a patchy pattern of unorganized sarcomeres with focal fibrosis and lipid droplet accumulation. Molecular profiling of atria using RNA sequencing showed differential expression of genes related to cellular stress, sarcomeric structure and fibrosis, including increased levels of
Anp
,
Malat1
and
Kcna1
.
Dchs2
displayed decreased expression in
Ttntv
atria.

Conclusion:
We identified an increased burden of rare, functional variation in genes associated with sarcomeric function in early-onset AF. Atrial myopathy with sarcomeric lesions, focal fibrosis, lipid droplet accumulation and altered gene expression of
Anp
,
Malat1
and
Kcna1
was found in atria of mice with
Ttntv
, suggesting a causal, pathophysiological relationship between
TTN
variants and AF. Interestingly,
DCHS2
displayed both increased burden of rare variation in early-onset AF and decreased expression in
Ttntv
mouse atria.
Abstract 15065: A Novel Predictor of Unsustained Return of Spontaneous Circulation in Patients in Cardiac Arrest Through a Combination of Capnography and Pulse Oximetry
Authors: Yang Jing , Tang Hanqi , Shao Shihuan , Xu Feng , Fu Yangyang , Xu Shengyong , Li Chen , Li Yan , Liu Yang , Walline Joseph H , Zhu Huadong , Chen Yuguo , Xu Jun
Published: December 2023

Introduction:
Unsustained return of spontaneous circulation (ROSC) is a critical barrier to survival in cardiac arrest patients. However, no parameter so far can be used to predict the sustainability of ROSC.

Research Questions:
End-tidal carbon dioxide (ETCO
2
) is regarded as an indicator of ROSC in cardiac arrest patients. Pulse oximetry photoplethysmogram (POP) parameters have been shown to be associated with peripheral perfusion in critically ill patients. We hypothesized that the combination of ETCO
2
and POP parameters might be discriminative for early recognition of patients at risk of unsustained ROSC before rearrest.

Aims:
This study examined whether ETCO
2
and POP parameters can be used to identify unsustained ROSC.

Methods:
We conducted a multicenter observational prospective cohort study of consecutive patients with cardiac arrest managed from 2013 to 2014. Patients’ general information, ETCO
2
, and POP parameters, including area under the curve (AUCp) and amplitude (Amp) of POP waveform, were collected and statistically analyzed.

Results:
The included 105 ROSC episodes (from 80 cardiac arrest patients) comprised 51 sustained ROSC episodes and 54 unsustained ROSC episodes. Patients with unsustained ROSC had lower 24-hour survival rate than sustained ROSC patients (11.5% vs. 25.0%, respectively; P<0.05). The logistic regression analysis showed that, ΔETCO
2
(difference in ETCO
2
between after to before ROSC) and ΔAUCp (difference in AUCp between after to before ROSC) were independently associated with sustained ROSC (OR = 0.931, P = 0.011 and OR = 0.998, P < 0.001). The area under the receiver operating characteristic curve of ΔETCO
2
, ΔAUCp, and the combination of both to predict unsustained ROSC were 0.752 (95% CI 0.660-0.844), 0.883 (95% CI 0.818-0.948), and 0.902 (95% CI 0.842-0.962).

Conclusion:
Patients with unsustained ROSC have a poor prognosis. Combined ΔETCO
2
and ΔAUCp showed significant predictive value for unsustained ROSC.
Abstract 15072: Lipoprotein(a) Regulates Vascular Redox State and Predicts Adverse Cardiovascular Outcomes in Coronary Artery Disease
Authors: Polkinghorne Murray D , Xie Cheng , CHAUHAN JAGAT SINGH , Baragetti Andrea , Patel Parijat , de Araujo Edmarcia , Wahome Elizabeth , Kotanidis Christos , Akoumianakis Ioannis , Krasopoulos George , Walcot Nicholas , Badi Ileana , Channon Keith M , Guzik Tomasz J , Norata Giuseppe Danilo D , Antoniades Charalambos
Published: December 2023

Introduction:
Lipoprotein(a) [Lp(a)] has an established link with cardiovascular disease yet the underlying mechanisms are incompletely understood.

Methods:
In 1472 cardiac surgery patients, we compared patients with any alternative allele from ≥3 of 7 Lp(a)-increasing SNPs (alternative variant group) to those with no alternative alleles in any of these SNPs (reference variant group). Plasma Lp(a) was measured using the Randox assay. The arterial redox state was measured using lucigenin chemiluminescence, where the contribution of NADPH-oxidases (NOX) and uncoupled nitric oxide synthases (eNOS) to superoxide (O
2
.-
) production was quantified. Arterial biopsies were used to perform RNA-sequencing. Patients were followed up for a median of 7.8 years.

Results:
Alternative variant patients had significantly higher plasma Lp(a) (A), plasma apolipoprotein-B (ApoB) (p<0.01), and arterial basal-O
2
.-
(B). Patients with medium/high vs low plasma Lp(a) had significantly increased plasma ApoB (p<0.0001) and arterial basal-O
2
.-
(C) as well as reduced tetrahydrobiopterin bioavailability (p<0.01). The association between Lp(a) and arterial basal-O
2
.-
was ApoB-independent. Non-diabetic patients in the alternative variant group and those with medium/high plasma Lp(a) had significantly increased arterial basal and eNOS-derived (p<0.05), but not NOX-derived, O
2
.-
. The transcriptomic profile of patients with high vs low plasma Lp(a) showed significantly downregulated PI3K-Akt signalling (D). Genetic tools revealed that Lp(a) is causally associated with an increased risk of cardiovascular death in an ApoB-independent manner (E). Patients with medium/high plasma Lp(a) also had a significantly increased risk of cardiovascular death (adj. HR=4.274 [95%CI: 1.227, 14.925], p=0.022).

Conclusions:
We demonstrate that Lp(a) increases arterial O
2
.-
through dysregulating vascular insulin signalling, mediating its association with cardiovascular disease.
Abstract 15073: Response to PCSK9 Inhibition in Homozygous Familial Hypercholesterolemia Patients is Variable in Different Regions of the World and According to Age
Authors: Raal Frederick J , Mehta Vimal , Kayikcioglu Meral , Blom Dirk J , Gupta Preeti , Durst Ronen , Asprusten Emil A , Turner Traci , Bahassi El Mustapha , Vest Jeffrey , Caldwell Kate , Kallend David , Stein Evan A
Published: December 2023

Background:
Reductions in LDL-C with PCSK9-inhibition in HoFH subjects are highly variable even within populations with the same pathogenic variants. Whilst initial studies were done in HoFH patients of European decent, recent studies from India and other countries with novel pathogenic variants as well as studies in paediatric patients have shown substantially less response to PCSK9 inhibition. In the global phase 3 LIBerate-HoFH trial, we evaluated two different PCSK9 inhibitors, lerodacibep (LIB) 300 mg SC QM and evolocumab (EVO) 420 mg SC QM in genetically confirmed HoFH patients on stable background lipid lowering therapy.

Methods:
Eligible patients (age ≥10 years) were randomized to either LIB or EVO for 24 weeks (Period A) followed by an 8 week ‘washout’ and crossed over to the alternate drug for the next 24 weeks (Period B). In a post-hoc analysis, the mean reduction in average LDL-C with both drugs were evaluated according to various world regions and age.

Results:
Of 65 who entered Period A, 56 completed both periods: 31 in USA/Europe/Israel/South Africa; 15 in India and 10 in Turkey. Mean baseline LDL-C was 401 mg/dL; 55% were female and 19(34%) were adolescents aged <18 years. For the total population, the mean (SE) reduction in average LDL-C was -9.6% (3.25) on LIB and -11.7% (3.65) on EVO (p=0.44, NS). LDL-C reductions varied considerably in different regions and response was poorer in the adolescent subjects. However, reductions in LDL-C of ≥15% were seen in 26.8% (n=15) with LIB and 37.5% (n=21) with EVO -
Table.

Conclusions:
Reductions in LDL-C achieved with PCSK9-inhibition in HoFH subjects are highly variable and differ according to region and age. However, given the clinically significant reductions in LDL-C in 1/3 of patients including patients from India and Turkey with null/null or novel variants, PCSK9 inhibition should remain part of standard of care for HoFH patients who remain with elevated LDL-C levels despite treatment with statin and ezetimibe.
Abstract 15087: First Clinical Trial in China to Evaluate the Efficacy and Safety of Moyoassist® Extra-VAD System
Authors: yue wang , Yuan Ningning , Hsu Po-Lin
Published: December 2023

Cardiogenic shock(CS)is associated with significant morbidity and mortality. For patients unresponsive to medicinal treatment, an alternative is a mechanical circulatory support (MCS) system. In China, common treatments using short-term MCS include IABP and VA-ECMO, both methods found their limitations. Therefore, a better strategy must be proposed to improve prognosis in CS patients, such as extracorporeal VAD (Extra VAD). Here, we reported 40 patients' data collected from a prospective, multicenter, single group clinical trial conducted from July 2021 to Feb 2023, which aims to evaluate the efficacy and safety of MoyoAssist® Extra-VAD system. MoyoAssist® is developed based on fully magnetically levitated pump technology to temporarily support the left, right, or biventricular circulation of patients with acute heart failure and cardiogenic shock of all causes. Patients were recruited for various indications, with PCCS (50%) and BTT (32.5%) being the top two causes. A combination of median sternotomy (22.5%), peripheral venous cannulation (52.5%) and mini-incision (25%) were employed to implant the device. Especially, jugular vein cannulation was a pioneering approach proposed to enable patients’ early ambulation and recovery. MoyoAssist® Extra-VAD has demonstrated stable and sufficient circulation support without severe device associated adverse events. The mean support duration was 7d16hrs, and overall survival rate at 30-day follow up was 62.5%. Hemodynamics indicated improvement with increased MAP and reduced CVP in all sub-groups. Lactate has shown a significant decrease in the PCCS-survival group (3.95 vs. 1.05, p<0.05), indicating improved reperfusion of organ tissues. While AST has shown a significant drop in the BTT-survival group (67.10 vs. 56.17, p<0.05), indicating improved liver function. During the support, 3 patients with peripheral cannulation and 2 patients with mini-incision were able to ambulate early. The types of complication seen were similar to those reported with CentriMag, but the rates of bleeding (15%) and hemolysis (0%) were much lower. In conclusion, MoyoAssist® Extra-VAD has demonstrated its safety and efficacy for short-to-mid-term support of patients with acute heart failure and cardiogenic shock.
Abstract 15088: Presence and Severity of Subclinical Atherosclerotic Disease in the Primary Prevention of the Oncologic Population
Authors: Diaz Saravia Sara , Gonzalez Sergio , Brenzoni Maria , Alarcon Pamela , Ferroni Fabian , Castellaro Carlos E , Chiabaut Jorge A , Melchiori Renzo
Published: December 2023

Introduction:
There is scarce evidence about endothelial dysfunction and damage in patients with a history of cancer in cardiovascular primary prevention and the impact in the development of Subclinical Atherosclerotic Disease (SCAD).

Methods:
A cross-sectional study was carried out on a registry of patients enrolled in primary prevention who had a Doppler ultrasound (DUS) screening for SCAD in the carotid and ileofemoral territory from 09/2020 to 04/2023. Inclusion criteria: 18 years old or older. Exclusion criteria: Previous cardiovascular and/or cerebrovascular event. History of cancer was defined as active or remitted cancer, excluding basal cell and squamous cell carcinoma. Population was divided in two, G1: non-oncologic group; G2 oncologic group. SCAD was defined as the presence of more than 1 atherosclerotic plaque in the carotid and/or ileofemoral territory. Univariate and bivariate analysis were done to establish population characteristics.

Results:
A total of 7920 patients were included: 7694 in G1 and 226 in G2 (97.15% vs 2.85%). G2 patients were older, mostly women and had higher prevalence of hypertension and dyslipidemia. Clinical characteristics and findings of the DUS are shown in Table1. A linear regression was done to assess the total plaque area compared to oncologic history, adjusted for age, sex, smoking history, dyslipidemia, obesity, sedentarism, diabetes, and hypertension. Results show that history of cancer is a predictor for SCAD (OR=1.43 [IC 95%: 1.1-1.9], p=0.021). Cancer also seems to be associated with a higher number of territories affected by SCAD (OR=1.63 [IC 95%: 1.2-2.1], 0.001) adjusted for age, sex, tobacco use, obesity, dyslipidemia, diabetes, sedentarism, and hypertension.

Conclusions:
Patients with history of cancer had more SCAD. Cancer behaved as a predisposing factor for increased plaque presence and area, adjusted for classic risk factors. This raises the need for more intensive control of SCAD in cancer patients.
Abstract 15090: Postural Orthostatic Tachycardia Syndrome After COVID-19 Vaccination
Authors: Teodorescu Debbie L , Kote Anxhela , Reaso Jewel , Rosenberg Carine , Liu Xiao , Kwan Alan C , Cheng Susan , Chen Peng-Sheng
Published: December 2023

Background:
COVID-19 vaccination may be associated with postural orthostatic tachycardia syndrome (POTS) incidence, but little is known of who is at risk, their autonomic state, or how they respond to therapy.

Methods:
This prospective cohort study analyzed clinical data of 10 POTS clinic patients with new-onset or worsening POTS after COVID-19 vaccination. We also compared heart rate variability (HRV, via spot and ambulatory electrocardiograms (ECGs)) and skin sympathetic nerve activation (SKNA) with 24 healthy controls.

Results:
Patient mean age was 41.5±7.9 years with equal gender balance. Ambulatory ECG showed no major arrhythmias. Mean standing norepinephrine level was 638.2±395.3 pg/mL, with 4 patients >600 pg/mL. All patients had conditions that could raise POTS risk: prior COVID-19 infection (N=4); hypermobile Ehlers-Danlos syndrome (N=6); mast cell activation syndrome (N=3 found pre-POTS, N=3 post-POTS); and autoimmune (N=7), cardiac (N=7), neurologic (N=6), or gastrointestinal conditions (4). HRV analysis indicated lower spot (36.09 ms±49.2) and ambulatory root mean square of successive differences (46.19 ms±24, p=0.042) vs control (72.49 ms±40.8). SKNA showed a reduced mean amplitude (0.97uV±0.052, p=0.011) vs control (1.2 uV±0.31) and burst amplitude (1.67 uV±0.16, p=0.018) vs control (4.3 uV±4.3). All patients received guideline-based POTS care. After 417.2±131.4 days of follow-up, 3 patients were on ivabradine, 2 on beta blockers, 2 on midodrine, 5 on antihistamines, 4 on mast cell stabilizers, and 1 on prednisone. All patients reported improvement, although 2 with COVID-19 reinfection and 1 with small fiber neuropathy did have relapses of POTS symptoms.

Conclusion:
POTS patients with post-vaccine onset or exacerbation had histories of potential predisposing conditions. These suggest a potential screening approach, though referral bias is possible. Elevated standing norepinephrine levels, decreased HRV, and decreased pRR50 support a sympathetic-dominant state. Though only 2/10 patients stayed on beta blockers, 8/10 did at least transiently use them. Reduced average SKNA and burst-to-mean amplitude ratio suggest the presence of peripheral autonomic neuropathy. Patients responded to standard POTS therapy.
Abstract 15092: Projected Cost Saving With Optimal Medication Adherence in Cardiovascular Disease Patients Requiring Lipid Lowering Agents in Mexico and Thailand
Authors: Cho Jeong-Yeon , Wilson Fernando A. , Chaikledkaew Usa , Phrommintikul Arintaya , Kim Kyoo , Chaiyakunapruk Nathorn
Published: December 2023

Background:
Adherence to chronic cardiovascular treatments is less than 50% in developing countries, which impedes achieving targeted clinical outcomes. This study aims to estimate potential benefits of improving adherence in CVD patients requiring secondary prevention.

Methods:
We performed state-transition Markov model simulation for secondary CVD prevention in Mexico and Thailand. Stakeholders were engaged based on CHEERS II guideline. The analyses were performed upon a healthcare system perspective for a lifetime horizon. Two scenarios were compared: (1)optimal adherence (which is simulated based on mean adherence from a meta-analysis of 51 RCTs), and (2) status quo. The association of adherence and CVD outcomes (MI and stroke) is based on a dose-response meta-analysis of observational studies of 4,051,338 patients. Direct medical costs are obtained from literature review. Outcomes are accumulated number of CVD events and associated costs in 2022 USD, life-year, and quality-adjusted life years (QALYs). Sensitivity analyses were performed to assess the robustness of our findings.

Results:
Status quo in both countries were expected to have a higher risk of CVD than optimal adherence (Mexico: RR 1.22, 95% CI 1.17-1.28; Thailand: RR 1.21, 95% CI 1.16-1.26). The number needed to treat to prevent one additional CV event was 25.02 and 29.37, respectively. Consequently, achieving optimal adherence can increase life-year by 0.60, 0.84 and QALYs by 0.59 and 0.68 in Mexico and Thailand, respectively. Moreover, this could avert CV event-related medical costs of $614 and $313. When lipid lowering therapy costs are included, the optimal adherence scenario results in cost saving with $418 in Mexico and $293 in Thailand. Cost saving findings are robust across all sensitivity analyses.

Conclusion:
In developing countries, patients requiring lipid lowering agents for secondary CVD prevention suffer from preventable outcomes due to their suboptimal medication adherence. It is recommended to consider various methods of improving adherence that could result in cost savings and achieving therapeutic goals.
Abstract 15096: miR-132 Inhibition Shows Anti-Hypertrophic Effects in Preclinical Heart Failure Models and in Exploratory Pharmacodynamic Parameters of a First-in-Human Phase 1b Clinical Trial
Authors: Batkai Sandor , Genschel Celina , Viereck Janika , Rump Steffen , Hauke Wilfried , Gyongyosi Mariann , Traxler Denise , Hinkel Rabea , Kupatt Christian , Levin Arthur A , Thum Thomas
Published: December 2023

Introduction:
Cardiac expression levels of miR-132 are elevated in patients with heart failure (HF) and have been associated and provoke pathological cardiac hypertrophy. To inhibit these cardiac remodeling processes and restore normal cardiac function, we developed the synthetic antisense oligonucleotide inhibitor CDR132L targeting miR-132. Anti-hypertrophic effects of miR-132 inhibition have been shown previously in cell culture models and a mouse model of pressure overload-induced HF.

Methods and Results:
MiR-132 inhibition with CDR132L was now tested in a mouse model of pressure overload induced HF induced by transverse aortic constriction (TAC) and in three different porcine HF models to further confirm the translatability of therapeutic effects. The first pig model was an early post-myocardial infarction (MI). Pigs were treated with CDR132L by intravenous (IV) or intracoronary (IC) infusion on day 3 and day 28 and analyzed on day 56 post-MI. As a second model, chronic post-MI HF pigs received monthly IV treatments over 3 or 5 months starting from month 1 post-MI. Third, percutaneous aortic constriction was induced in pigs by reduction stent implantation and CDR132L was administered IC on day 0 and day 28 followed by analysis on day 56. Hypertrophy was determined by cell size measurements in wheat germ agglutinin (WGA) stained cardiac sections and was significantly decreased between 15% and 29% in CDR132L-treated groups with sufficient dose levels compared to placebo-treatment independent from the large animal model and dosing regimen. Furthermore, TAC mice treated with CDR132L showed a significant decrease in left ventricular mass by 14 % compared to placebo. In line with these data, the cardiac remodeling marker lipocalin-2 (NGAL) was reduced in plasma of chronic HF patients assessed in a first-in-human phase 1b clinical to test safety, efficacy, and also exploratory pharmacodynamics of CDR132L (NCT04045405).

Conclusions:
Our results confirm beneficial effects of CDR132L treatment on pathological cardiac remodeling in HF.
Abstract 15115: Efficacy and Safety of miR-132 Inhibitor CDR132L in Patients With Reduced Left Ventricular Ejection Fraction After Myocardial Infarction: Rationale for and Design of the HF-REVERT Trial
Authors: Bauersachs Johann K , Solomon Scott , Anker Stefan D , Antorrena Miranda Maria Isabel , Batkai Sandor , Filippatos Gerasimos , Ponikowski Piotr , Vardeny Orly , Hauke Wilfried , Thum Thomas
Published: December 2023

Background:
Inhibition of miR-132 effectively prevents and reverses heart failure (HF) in relevant models, making it an attractive HF target. CDR132L is a synthetic antisense oligonucleotide (ASO) selectively blocking miR-132. Translational
in vitro
and
in vivo
studies have demonstrated meaningful efficacy of CDR132L on left ventricular (LV) structure and function. CDR132L was safe and well tolerated in a Phase 1b study in chronic HF patients. The indicative effects of the miR-132 inhibitor CDR132L may be particularly beneficial in patients with active adverse remodelling, e.g. after acute myocardial infarction with early decline in ejection fraction. These patients have been relatively understudied and therapeutic options are limited.

Method:
The HF-REVERT (P
h
ase 2, Multicenter, Randomized, Parallel, 3-arm, Placebo-controlled Study to Assess E
f
ficacy and Safety of CD
R
132L in Pati
e
nts with Reduced Left
V
entricular
E
jection F
r
ac
t
ion (≤ 45%) after Myocardial Infarction; NCT05350969) is a proof-of-concept study to evaluate the efficacy of CDR132L in improving cardiac function and safety in patients with reduced LV ejection fraction (LVEF). HF-REVERT aims to assess the efficacy and safety of 5 mg/kg and 10 mg/kg CDR132L, given as 3 single intravenous doses administered 28 days apart as an add-on to standard-of-care treatment, in a larger cohort of patients (N = 280) with HF and reduced LVEF (≤ 45%) after MI with a follow-up of 10 months. Key inclusion criteria are the diagnosis of acute STEMI/NSTEMI and the development of systolic dysfunction (LVEF ≤ 45%) after MI index event and elevated N-terminal pro B-type natriuretic peptide (NT-proBNP). The study consists of a 6-month double-blind treatment period with a read out of the primary endpoint LVESVI (left ventricular end systolic volume index) followed by a 6-month open label observation period.

Discussion:
The HF-REVERT trial currently tests CDR132L in patients with MI and systolic dysfunction. This trial may therefore underpin the concept of miR-132 inhibition to prevent/reverse cardiac remodeling in HF patients. The results will inform the design of a subsequent outcome trial to test the effect of CDR132L in HF patients.
Abstract 15123: Adult Human Cardiomyocyte Mechanics in Osteogenesis Imperfecta
Authors: Lee Benjamin W , Caporizzo Matthew , Chen Yingxian , Bedi Kenneth , Prosser Benjamin , Margulies Kenneth B , Vite Alexia
Published: December 2023

Introduction:
Osteogenesis imperfecta (OI) is an extracellular matrix (ECM) disorder characterized by defects in collagen 1 transport or synthesis. While reduced collagen in OI hearts have been associated with reduced myocardial stiffness and left ventricular remodeling, its consequences on cardiomyocyte (CM) function have not been studied. Here we explore the tissue-level and CM-level properties of a heart from a deceased organ donor with OI Type I (heterozygous c.1821+1G>A mutation in COL1A1).

Methods:
The OI heart and non-failing (Control) hearts were obtained at the time of organ donation and arrested using ice-cold cardioplegia. Portions of the left ventricle were flash frozen or fixed for molecular assays. Trabeculae were dissected and passive mechanics assessed. The left anterior descending artery was cannulated and perfused with collagenase to isolate single CMs, which were then cultured on physiologic (10 kPa) or pathologic (50 kPa) stiffness substrates. CM contractility was assessed after 24 or 48 hours of culture.

Results:
Immunoblot and histology confirmed approximately 50% reduction of collagen 1 in OI vs. Control. Trabecular stretch demonstrated low stiffness at the tissue level. Isolated CMs from the OI heart were hypercontractile relative to non-failing controls after 24 hours of culture regardless of culture stiffness. In response to 48 hours of culture, OI CMs demonstrated an exaggerated stiffness-dependent reduction in contractility (sarcomere shortening on 50 kPa substrate- Controls: 0.10±0.01 μm vs. OI: 0.04±0.07 μm, p<0.01) suggesting that OI CMs may have an impaired stress response. Levels of detyrosinated tubulin, known to be responsive to ECM stiffness, were 30% reduced in OI.

Conclusions:
These data confirm CM level adaptations to reduced ECM stiffness that extend our understanding of OI in the heart and suggests that CMs adapted to a constitutively low stiffness environment may be less able to respond to increased external loads.
Abstract 15130: Sweat Lactate Sensor for Detecting Anaerobic Threshold in Paitents With Heart Failure: Prospective Clinical Trial (LacS-001)
Authors: Kawakubo Ichihara Yumiko , Yamaoka Kouki , Ryuzaki Toshinobu , Ikura Hidehiko , Nakashima Daisuke , Shiraishi Yasuyuki , Ieda Masaki , Yoshinori Katsumata
Published: December 2023

Background:
Exercise is essential for good health and prevention of exacerbations in patients with heart failure (HF). To determine ventilatory threshold (VT); a key to detect appropriate exercise intensity, our team developed a small, easy-to-use device for non-invasive, simple, and real-time visualization of sweat lactate dynamics during exercise.

Clinical Question:
Could our sweat lactate sensor (GI-1) provide a safe and accurate means of detecting VT in patients with HF in a clinical setting?

Aim:
This prospective clinical trial (clinical trial; jRCT2032220057) was designed to investigate the safety of a sweat lactate sensor (GI-1) and the correlation between the lactate threshold in sweat (sLT), as assessed using our sweat lactate sensor, and the VT.

Methods:
We recruited 50 patients with HF and New York Heart Association functional classification I-II, with a median age of 63.5 years (interquartile range: 58.0-72.0 years). Incremental exercise tests were conducted and changes in sweat lactate levels were monitored simultaneously. The sLT was defined as the first steep increase in lactate levels from baseline as seen on graphical plots and was evaluated by three independent investigators. The primary outcome measures were a correlation coefficient of 0.6 or greater between sLT and VT, the similarities as assessed by the Bland-Altman analysis, and the standard deviation of the difference between the two within 15 W.

Results:
Among the 50 patients, a correlation coefficient of 0.651 (95% confidence interval, 0.391-0.815) was achieved in 32 cases. The difference between the sLT and VT was -4.9±15.0 W, and no comparative error was noted in the Bland-Altman plot. No device-related adverse events were reported among the registered patients.

Conclusions:
Our sweat lactate sensor, GL-1, provides a safe and accurate means of detecting VT in patients with HF in a clinical setting, thereby offering valuable additional information for treatment.
Abstract 15135: Timing of Percutaneous Coronary Intervention and Risk of New-Onset Acute Ischemic Stroke in Non-ST Elevation Myocardial Infarction: An Insight of National Inpatient Sample 2016-2019
Authors: Shi Bo , JIA Shaobin , Ma Xueping , CONG Guangzhi
Published: December 2023

Introduction:
Current guidelines recommend an early invasive strategy within 24 hours only in high-risk non-ST elevation myocardial infarction (NSTEMI). New-onset acute ischemic stroke (NAIS) is a rare but fatal complication of percutaneous coronary intervention (PCI). However, the effect of the timing of the PCI and the risk of NAIS in NSTEMI is not well defined.

Hypothesis:
Late PCI is associated with NAIS risk in NSTEMI.

Methods:
NSTEMI patients who underwent PCI were queried from the National Inpatient Sample Database (2016-2019) and stratified into three groups: early (<24 h), medium (24-72 h), and late PCI (>72 h). Multivariable logistic regression models were used to determine the timing of PCI and NAIS, adjusted for demographics, comorbidities, and hospital characteristics.

Results:
Among 633,115 weighted hospitalizations in 2016-2019, late PCI patients had a higher incidence of NAIS (1.3%) compared to early (0.67%) and medium PCI (0.71%). Late PCI patients were older, more likely to be female, and had a higher prevalence of comorbidities (diabetes mellitus, congestive heart failure, chronic pulmonary and renal disease, and atrial fibrillation) than early and medium PCI. After adjustment, only late PCI was significantly associated with a 55% increased NAIS risk (adjusted OR: 1.55 [95% CI: 1.30-1.84]). There was heterogeneity in the magnitude of risk by age and gender. Younger people (<65 years) (
p
for interaction <0.0001) and males (interaction -value
p
=0.0433) were more likely to encounter NAIS. The incidence of NAIS increased from 2016 to 2019 in both medium and late PCI.

Conclusions:
Late PCI over 72 hours was associated with a higher risk of NAIS than PCI performed within 24 hours, particularly among young and male people.
Abstract 15171: Endothelium-Derived C-Type Natriuretic Peptide Prevents the Development and Progression of Abdominal Aortic Aneurysm
Authors: Aubdool Aisah A , Moyes Amie J , Perez-Ternero Cristina , Tsui Janice C , Lu Hong S , Daugherty Alan , Hobbs Adrian J
Published: December 2023

Background:
Abdominal aortic aneurysm (AAA) is a life-threatening disease characterised by dilatation, inflammation and structural weakness of the abdominal aorta. Since the only effective existing intervention is surgery, development of pharmacological therapies is desperately needed. C-type natriuretic peptide (CNP) is a key endothelium-derived molecule that possesses vasodilator, anti-inflammatory and anti-atherogenic activity. Thus, we explored the role and therapeutic potential of CNP in AAA pathogenesis.

Methods:
Suprarenal aortic diameter was assessed by ultrasonography at baseline and following Angiotensin II (AngII, 1.44mg/kg/day) infusion in wild type (WT) or endothelium-restricted CNP deficient (ecCNP
-/-
) mice infected with an AAV-expressing proprotein convertase subtilisin/kexin type 9 gain-of-function mutation (D377Y) or backcrossed on an apolipoprotein E deficient (ApoE
-/-
) background. At 28 days, aortas were harvested for qRT-PCR, pharmacological assessment of vasorelaxant activity and histological analysis; plasma CNP concentrations were also determined. In some studies, CNP (0.2mg/kg/day) was infused to rescue any adverse phenotype.

Results:
ecCNP
-/-
exhibited an aggravated AAA phenotype compared to WT, exemplified by greater dilation, fibrosis and elastin degradation (without changes in blood pressure). Whilst plasma CNP concentrations were reduced in murine AAA, CNP mRNA abundance was elevated within aneurysmal tissue of ecCNP
-/-
, accompanied by increased abundance of mRNA encoding markers of inflammation (
IL-6, Adgre1, VCAM-1, CCL-2
), extracellular matrix remodelling/calcification (
MMP-2, Notch-1, BMPR2, smoothelin
), fibrosis (
fibronectin
) and apoptosis (
Bax
)
.
CNP-induced relaxations were enhanced in aortic rings from aneurysmal tissue compared to control; an effect possibly underpinned by upregulation of natriuretic peptide receptor expression. Prophylactic administration of CNP protected against the severity of AngII-induced AAA.

Conclusions:
Endothelial CNP plays an important role in attenuating AAA formation by preserving aortic structure and function. Therapeutic strategies aimed at mimicking CNP bioactivity may prevent the clinical progression of AAA.
Abstract 15172: P21 Activated Kinase 2 Mediates Cardioprotection in Heart Failure With Preserved Ejection Fraction by Modulating Endoplasmic Reticulum Stress Response
Authors: Zhang Hongyuan , Azam Tayyiba , Zi Min , Wang Xin
Published: December 2023

Introduction:
Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure characterised by diastolic dysfunction but normal systolic function. Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of HFpEF. Previous studies have reported that P21 activated kinase 2 (Pak2) confers cardioprotection against the endoplasmic reticulum stress response.

Hypothesis:
Pak2 protein can potentially alleviate the adverse effects of maladaptive ER stress in HFpEF.

Methods:
The HFpEF model was developed by feeding C57/BL6N male mice with a high-fat diet (HFD) and a constitutive nitric oxide inhibitor, L-NAME, in drinking water for 15 weeks. Cardiac function was assessed by echocardiography and hemodynamics. Heart and lung structure was detected by H&E staining and Masson staining. Electron microscopy, immunoblotting, and RNA sequencing were used to investigate the ER structure and function. Cardiomyocyte-specific Pak2 knockout (Pak2
CKO
) mice and adeno-associated virus (AAV) 9 for Pak2 overexpression were used to investigate the role of Pak2 in the heart.

Results:
After 15 weeks of feeding, mice on the HFD+L-NAME diet developed an HFpEF phenotype, as indicated by cardiac hypertrophy, impaired diastolic function but preserved systolic function, and pulmonary remodelling. The ER structure and the IRE1/XBP1s pathway were impaired in the cardiomyocytes of HFD+L-NAME mice. Pak2CKO mice exhibited the HFpEF phenotype at 10 weeks. In addition, Pak2 overexpression prevented diastolic dysfunction after 15 weeks and preserved the activation of the IRE1/XBP1s pathway under stress conditions.

Conclusions:
HFD + L-NAME diet for 15 weeks recapitulated the features of HFpEF in mice. Pak2 plays a protective role in HFpEF progression by modulating the cardiomyocyte ER stress response through the IRE1/XBP1s signaling pathway.