bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4141755: New internet-based warfarin anticoagulation management approach after mechanical heart valve replacement: prospective, multicenter, randomized controlled trial
Authors: Zhu Zhihui , He Meng , Zhang Haibo , Lai Yongqiang
Published: November 2024

Background:
Mechanical heart valve replacement (MHVR) is an effective method for the treatment of severe heart valve disease. However, it subjects patients to lifelong warfarin therapy after MHVR, with the attendant risk of bleeding and thrombosis. Whether internet-based warfarin management reduces complications and improves patient quality of life remains unknown.

Objective:
This study aimed to compare the effects of internet-based warfarin management and the conventional approach in patients who received MHVR in order to provide evidence regarding alternative strategies for long-term anticoagulation.

Methods:
This was a prospective, multicenter, randomized, open-label, controlled clinical trial with a 1-year follow-up. Patients who needed long-term warfarin anticoagulation after MHVR were enrolled and then randomly divided into conventional and internet-based management groups. The percentage of time in the therapeutic range (TTR) was used as the primary outcome while bleeding, thrombosis, and other events were the secondary outcomes.

Results:
A total of 721 patients were enrolled. The baseline characteristics did not reach statistical differences between the two groups, suggesting the random assignment was successful. As a result, the internet-based group showed a significantly higher TTR (mean 0.53, SD 0.24 vs. mean 0.46, SD 0.21; P < .001) and fraction of time in the therapeutic range (mean 0.48, SD 0.22 vs. mean 0.42, SD 0.19; P < .001) than did those in the conventional group. Furthermore, as expected, the anticoagulation complications, including bleeding and embolic events, had a lower frequency in the internet-based group than in the conventional group (6.94% vs. 12.74%; P = .01). Logistic regression showed that internet-based management increased the TTR by 7% (odds ratio [OR] 1.07, 95% CI 1.05-1.09; P < .001) and reduced the bleeding and embolic risk by 6% (OR 0.94, 95% CI 0.92-0.96; P = .01). Moreover, low TTR was found to be a risk factor for bleeding and embolic events (OR 0.87, 95% CI 0.83-0.91; P = .005).

Conclusions:
Internet-based warfarin management is superior to the conventional method, as it can reduce anticoagulation complications in patients who receive long-term warfarin anticoagulation after MHVR.
Abstract 4141772: “SETDB2 regulates the Innate Immune Memory response and influences Inflammatory Immune landscape in Atherosclerosis”
Authors: JAISWAL ANANT , Halasz Laszlo , Suarez Yajaira , Fernandez-Hernando Carlos , Osborne Timothy
Published: November 2024

Background:
Several pro-inflammatory signals, including microbial cell components such as β-glucan or metabolites produced during western-diet feeding, function as initial “triggers” that train macrophages to respond more robustly to a later secondary inflammatory challenge. This crude “memory” response in innate immune cells is termed as “trained immunity." This memory response is mediated, at least in part, through epigenomic changes to the chromatin landscape.

Aim:
Role of SETDB2 in trained immunity and atherosclerosis.

Results:
Our preliminary findings suggest that SETDB2, a putative epigenomic enzyme that is a member of the KMT1 family of lysine methyltransferases, is induced by β-glucan training in macrophages, and knocking out SETDB2 in myeloid cells (SETDB2mKO) altered the magnitude of the secondary pro-inflammatory response in the two-step training protocol described in Background. RNA sequencing revealed a dynamic profile of transcripts that were altered in SETDB2mKO with different gene clusters, consistent with SETDB2 positively regulating some genes while negatively regulating others. We also developed SETDB2 knock-in (SETDB2KI) mice that crippled its potential enzymatic function. Interestingly, SETDB2KI data suggested that SETDB2’s enzyme activity is essential for its role in negatively regulating genes, while positively regulated genes require SETDB2 but not its enzyme activity. Several metabolic and inflammatory pathway genes were regulated by SETDB2, as were several genes known to be involved in immune cell infiltration. Bone marrow transplantation from global SETDB2-deficient mice into LDLRKO resulted in more severe atherosclerotic plaques following western diet feeding, and single-cell RNA sequencing revealed increased neutrophil and reduced CD4+ T-cell populations in lesions from the SETDB2-deficient plaques. When combined together, the positive and negative regulation of different gene clusters by SETDB2 in the in-vitro training study and the more severe atherosclerosis with altered immune profiles in the SETDB2-deficient plaques in vivo suggest that SETDB2 positively and negatively regulates CD4+ T cell and neutrophil recruitment to atherosclerotic plaques, respectively.

Conclusion:
Our preliminary findings show that SETDB2 regulates immuno-metabolic pathway genes via two different mechanisms, which might also influence the immune cell inflammatory landscape and severity of atherosclerosis.
Abstract 4141774: Plasma omega-3 fatty acids/omega-6 fatty acids and arterial stiffness in middle aged healthy Japanese cohort
Authors: Matsumoto Chisa , Tomiyama Hirofumi , Nakano Hiroki , Takahashi Takamichi , Kani Junya , Shiina Kazuki , Yamashina Akira , Satomi Kazuhiro
Published: November 2024

Background:
Numerous studies evaluating the effects of consumption of omega-3 fatty acids (ω3FAs) and omega-6 fatty acids (ω6FAs) on the prevention of cardiovascular disease (CVD) have yielded inconsistent results. In addition, the association between ω3FAs/ω6FAs and CVD has been suggested to vary with the daily intake levels of fatty acids among individuals. On the other hand, the longitudinal associations between plasma ω3FAs/ω6FAs and arterial stiffness, which is a predictor of CVD, have not been well elucidated.

Hypothesis:
We hypothesized that plasma ω3FAs are associated with the suppression of age-related increases in arterial stiffness, whereas plasma ω6FAs are associated with an increase in arterial stiffness.

Aims:
The objective of this study is to fill the existing research gap by investigating the longitudinal association between plasma ω3FAs/ω6FAs and arterial stiffness in a Japanese people, known for their higher intake of marine products.

Methods:
This prospective observational study included 2520 healthy Japanese participants (mean age:43.1±8.7y, men:83.1%) who underwent repeated annual health check-ups from 2008 to 2013. Participants with a history of CVD or treatment for CVD risk factors were excluded. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV), and plasma ω3FAs [docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)]/ω6FAs [arachidonic acid (AA), dihomo-gamma-linolenic acid (DGLA)] were evaluated by gas chromatography. The longitudinal association between plasma ω3FAs/ω6FAs and baPWV was evaluated by a linear mixed model adjusted for conventional CVD risk factors.

Results:
During a median follow-up of 5 years (IQR 4-5 years), 11034 baPWV measurements were performed. The linear mix model adjusted for conventional CVD risk factors revealed that both higher plasma AA and DGLA levels were significantly associated with an increase in baPWV (1SD increase in AA; β=12±3, 1SD increase in DGLA; β=14±3, both P<0.001). However, neither plasma EPA nor DHA levels were longitudinally associated with the baPWV.

Conclusion:
Plasma ω3FAs were not longitudinally associated with arterial stiffness. In contrast, higher plasma ω6FAs levels were longitudinally associated with increased arterial stiffness. Our results suggest that the potential CVD-preventive effects of ω3FAs may not involve the suppression of arterial stiffness. Conversely, the increased CVD risk associated with ω6FAs may be attributed to increased arterial stiffness.
Abstract 4141779: Metabolomic Markers of Aortic Stenosis Development: the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Shelbaya Khaled , Lamberson Victoria , Yang Yimin , zhou peidi , Alkis Taryn , Matsushita Kuni , Yu Bing , Shah Amil
Published: November 2024

Background:
Prior metabolomics studies in aortic stenosis (AS) have focused on patients with severe stenosis and their response to intervention. Limited data exist regarding circulating metabolites predictive of AS development.

Aim:
Identify circulating metabolites associated with aortic valve (AV) hemodynamics and incident AV events.

Hypothesis:
We hypothesized that large-scale metabolomics can identify novel circulating metabolites relevant to AS development.

Methods:
Among participants in the community-based ARIC cohort study who underwent protocol echocardiography and metabolomic profiling by chromatography mass spectrometry (Metabolon) at study Visit 5 (2011-2013) and were free of AV replacement, we related metabolite values to AV peak velocity (AVmax) and dimensionless index (DI) cross-sectionally and to incident AV events using multivariable linear and Cox regression models. Metabolites with ≤10% missingness (n=736 metabolites) were included and normalized using log2 transformation. Post-Visit 5 AV events were ascertained based on ICD codes for AV-related hospitalization and interventions. Regression models were adjusted for age, sex, race, center, heart rate, blood pressure, estimated glomerular filtration rate, and cardiovascular (CV) risk factors and diseases. Statistical significance was based on a False Discovery Rate (FDR) <0.05.

Results:
Among 5,107 participants included, mean age was 75±5 years, 57% were women, and 18% reported Black race. Mean LVEF was 65 ±7%, AVmax 1.3 ±0.4 m/s, and DI 0.76 ±0.14. After adjusting for CV risk factors and disease, 80 metabolites were cross-sectionally associated with AVmax at FDR <0.05, 28 of which were further associated with DI (
Figure A
). Over a median follow-up of 8 [Q1- Q3, 7-9] years, 245 experienced an AV-related hospitalization. Of the 28 metabolites associated with AV hemodynamics, 20 were associated with incident AV-related hospitalization (
Figure B
). Amino acids and amino sugar metabolites were associated with greater hemodynamic AV stenosis and a higher risk of AV events, while higher dicarboxylic fatty acids and other lipids values were associated with better AV hemodynamics and a lower risk of AV-related hospitalization (
Figure C
).

Conclusion:
Large-scale metabolomics in an older community-based cohort identifies novel circulating markers of AS risk. While amino acid metabolites associated with high risk, dicarboxylic fatty acids were associated with lower risk.
Abstract 4141782: Maladaptive alterations in the biomechanics of the post-myocardial scar as a consequence of CD8
+
T-cell transfer
Authors: Dasgupta Shaoni , Learmonth Maya , Corker Alexa , Troncoso Miguel , Broughton Philip , Baicu Catalin , Bradshaw Amy , Zile Michael , Deleon-Pennell Kristine
Published: November 2024

CD8
+
T-cells are adverse regulators post myocardial infarction (MI), leading to increased mortality and impaired cardiac function. We hypothesize that CD8
+
T-cells impair cardiac function by altering scar composition.

MI was induced by ligating the left anterior descending coronary artery in C57BL6/J (WT; 3-7 months of age, n≥2/sex) and CD8a
tm1mak
mice (CD8
-/-
; 3-7 months of age, n≥2/sex/treatment). CD8
-/-
mice were injected with either vehicle or naïve splenic CD8
+
T-cells (2x10
6
cells/injection) via tail vein, 4 hours post-MI. Infarct tissue was collected post-MI Day 7 and underwent biomechanical, histological, and biochemical analyses. Effects of granzyme (Gzm) A, B, and K on collagen cleavage were tested using a fluorogenic collagen cleavage assay to examine possible mechanisms of scar alteration.

Mice lacking CD8
+
T-cells had improved ejection fraction and decreased dilation (p<0.05 for both) compared to WT mice at post-MI Day 7. This protective effect was lost in CD8
-/-
mice that received splenic CD8
+
T-cells (p=0.09 vs WT). Biomechanical testing revealed CD8
-/-
mice had a 2-fold increase in regional scar stiffness compared to WT mice (p<0.05). Re-supplementation with splenic CD8
+
T-cells decreased scar tissue stiffness compared to vehicle treated mice (p<0.05) mimicking biomechanics of WT mice. Picrosirius red staining showed no significant differences in total collagen levels (p=0.51) across all groups. However, further investigation using collagen hybridization peptide staining showed increased collagen cleavage in WT mice in comparison to CD8
-/-
mice (p<0.05) as demonstrated by overall fluorescence intensity. Evaluation of percent area of CHP staining showed WT mice had increased cleavage distribution within the infarct compared to vehicle-treated CD8
-/-
mice (p<0.05). This effect was lost with CD8
+
T-cell supplementation (p=0.13 vs WT).
Ex-vivo
cleavage assay demonstrated GzmA and K cleaved collagen in a concentration (0-50 AU) and temporal-dependent manner (0-24 hrs). Both GzmA and K demonstrated a 10-fold greater capacity in collagen cleavage compared to GzmB at 25 AU, implicating distinctly separate roles for the different granzymes during post-MI scar formation and maturation.

In conclusion, our data demonstrates that CD8
+
T-cells regulate cardiac fibrosis in part through the release of granzymes, leading to impairments of biomechanical capability of the left ventricle and increased LV dilation.
Abstract 4141892: Insulin-like growth factor binding protein 7 induces cell senescence in vitro and is associated with cell senescence in the advanced atheroma.
Authors: Sukhanov Sergiy , Higashi Yusuke , Snarski Patricia , Danchuk Svitlana , Delafontaine Patrice
Published: November 2024

BACKGROUND:
Cellular senescence, an irreversible cell cycle arrest, has been associated with coronary heart disease (CHD). Senescent cells (SC) secrete proinflammatory molecules contributing to CHD. Insulin-like growth factor I (IGF1) protects against developing cell senescence and atherogenesis. IGF1 binding protein 7 (BP7) binds IGF1 and also interacts with IGF1 receptor (IGF1R), suppressing intracellular IGF1 signaling.

HYPOTHESIS:
SC secrete BP7, and BP7 promotes cell senescence via suppression of IGF1 signaling.

METHODS:
Cell senescence was induced by treatment of smooth muscle cells (SMC) with Bleomycin. Cell proliferation was quantified by live cell analysis system. BP7 levels were measured by Westerns in cell lysates and conditioned medium (CM) and by immunohistochemistry in atherosclerotic pigs. BP7/IGF1R binding was quantified by proximity ligation assay (PLA).

RESULTS:
Bleomycin arrested SMC proliferation at 16h, upregulated senescence markers (beta-galactosidase and γH2A.X histone), and elevated BP7 levels in CM (3-fold increase, P<0.05) showing that SC secrete and upregulate BP7. We obtained CM from SC and used it to treat non-senescent SMC. CM inhibited IGF1-induced Akt phosphorylation in non-senescent cells, and CM incubation with BP7 antibody reversed this effect, indicating that BP7 mediates CM inhibitory effect on IGF1 signaling. BP7 overexpression (with pCMV-IGFBP7 vector) or inhibition of IGF1R (using Ganitumab, IGF1R antibody) suppressed cell proliferation, and upregulated senescence markers. BP7 overexpression also blocked IGF1-induced cell proliferation and migration (both are P<0.05) consisted with BP7 inhibitory effect on IGF1 signaling. Increased BP7 levels was detected in SMC in the fibrous cap (FC) in porcine plaque compared to BP7 level in vascular media (1.8-fold increase, P<0.05). BP7 upregulation in plaque correlated with elevated PLA signal indicating increased BP7/IGF1R binding. We used spatial transcriptomics to profile gene expression in the porcine atheroma. BP7 upregulation was detected in FC cluster (P<0.001) and it was co-localized with increased senescence module score.

CONCLUSIONS:
SC upregulate BP7 and BP7 inhibits IGF1 signaling. Upregulated BP7 induces senescence in vitro and it was associated with SC in the advanced coronary plaque. Our results suggest a novel role of BP7 in senescence and atherogenesis and identify BP7 as a potential target for anti-atherogenic therapy.
Abstract 4142745: Lipoprotein(a) distribution across autoimmune inflammatory diseases: a pooled analysis from 28 Phase III clinical trials
Authors: Wilkinson Michael , Khakwani Aamir , Zaoli Silvia , Khatri Manish , Schludi Belinda , Hu Xingdi , McElligott Sean
Published: November 2024

Background:
Lipoprotein(a) [Lp(a)] is largely determined by genetic factors and is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). Real-world evidence is limited due to low rates of Lp(a) testing, and little is known regarding the Lp(a) distributions in diseases beyond ASCVD, including autoimmune inflammatory diseases.

Methods:
This cross-sectional study identified adult patients with available Lp(a) levels at baseline (before randomization) from 28 Phase III randomized clinical trials across autoimmune inflammatory diseases: rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PA), and ankylosing spondylitis (AS). Individuals from clinical trials for ASCVD were used as the reference group. Multivariable logistic regression analysis was performed to assess whether patients with certain autoimmune diseases were more likely to have Lp(a) ≥30mg/dL (≥75nmol/L) compared with ASCVD.

Results:
We identified 12,799 adults from RA (1287, 10%), psoriasis (5578, 44%), PA (1928, 15%), AS (1146, 9%), and ASCVD (2860, 22%) trials. Overall, the mean age (SD) was 50.4 (14.6) years, 41% female, 2.7% Black individuals, 15.2% Asian individuals, 37.7% history of ever smoking, and 77.8% with diabetes. Lp(a)>=30mg/dL was most common among those with RA (57%), followed by PA (46%), ASCVD (43%), AS (42%) and psoriasis (39%). A consistent Lp(a) distribution across diseases was seen for Lp(a)≥50mg/dL (Figure). Adjusting for age, sex, race, BMI, diabetes, total cholesterol, lipid lowering therapies and C-reactive protein (CRP), patients with RA and PA were 72% and 39% more likely to have Lp(a)>=30mg/dL compared with ASCVD (p<0.05). CRP was also significantly associated with Lp(a)>=30mg/dL: Odds Ratio (OR) = 1.07 (1.05 – 1.10), p<0.0002).

Conclusion:
In this pooled analysis of Phase III trials, increased levels of Lp(a) were observed among patients with RA, psoriasis, PA and AS with patients with RA and PA more likely to have Lp(a)≥30mg/dL than patients with ASCVD. Future research with longitudinal Lp(a) levels is important to clarify the interplay between inflammation, Lp(a), and ASCVD risk, especially in autoimmune diseases associated with increased Lp(a) levels.
Abstract 4142818: Odorgenetics-based noninvasive and precise neuromodulation of cardiac ganglia plexus prevents myocardial ischemia-induced ventricular arrhythmia
Authors: Zhou Liping , Liu Chengzhe , Jiang Hong , Yu Lilei
Published: November 2024

Background:
Autonomic imbalance exacerbates arrhythmia after myocardial infarction. Previous studies have utilized optogenetics and other techniques to modulate cardiac autonomic rebalance and significantly suppressed arrhythmia. However, electrical or optogenetic modulation requires implantation of device with electrodes or opto-electrodes, which is invasive and has a limited battery life.

Research Questions:
Odorgenetics technology is based on the binding of volatile odor molecules to specific G-protein coupled olfactory receptors to rapidly activate neurons. This study aimed to utilize odorgenetics to noninvasively and precisely modulate cardiac ganglia plexus (GPs) to prevent myocardial ischemia-induced ventricular arrhythmias (VAs).

Methods:
Canines were divided into the control group (n=6) and the odorgenetics group (n=6). pAAV-CMV-Or35a-Or83b-EGFP-tWPA was microinjected into GPs to specifically express olfactory receptors Or35a-Or83b in the odorgenetics group. Four weeks after injection, the volatile odorant molecule 2-pentanone was delivered via inhalation to activate Or35a-Or83b for GP modulation. Myocardial ischemia was induced by 1h left anterior descending occlusion followed with 1h reperfusion. GP odorgenetic stimulation was performed for 2h simutaneously. GP function and neural activity, effective refractory period (ERP), and VAs were measured.

Results:
Neurons in the GPs were transfected EGFP
+
in the odorgenetics group. Compared to the control group, inhalation of the odorant molecule 2-pentanone significantly activated GP function and neural activity in the odorgenetics group. Moreover, odorgenetic modulation showed a fast on-off effects on GP neural activity, that is, it can rapidly and reversibly modulate GP neural function and activity. In the control group, myocardial ischemia shortened ERP and increased spatial dispersion, which was improved by GP odorgenetic stimulation. In addition, myocardial ischemia induced VAs were significantly decreased by GP odorgenetic modulation (number of VT/VF: 3.5±4.5 vs. 14.8±7.7, P<0.05 vs. control group).

Conclusion:
Odorgenetics technology enables noninvasive and fast on-off neuromodulation of cardiac GP, and thus prevents myocardial ischemia-induced VAs.
Abstract 4142825: Anisotropic conductive hydrogel reduces the incidence of major adverse cardiac events in a beagle model of myocardial infarction
Authors: Wang Xiaofei , Zhang Zizhuo , Wang Jiale , Yu Lilei
Published: November 2024

Background:
The main adverse cardiac events after myocardial infarction (MI), including ventricular arrhythmia and heart failure, have an important impact on the survival rate and long-term prognosis of patients with MI. Hydrogel patch is a promising treatment method, but it has some disadvantages such as low bionic performance.

Research Questions:
The purpose of this proof-of-concept study was to investigate the cardiac protection potential of PPy-chitin hydrogels in beagle models of MI.

Methods:
In beagle MI models, body surface electrocardiogram and event-related potential were used to evaluate cardiac electrophysiology. Induced arrhythmias was assessed by programmed electrical stimulation. Transthoracic echocardiography was used to evaluate left ventricular function.

Results:
PPy-chitin hydrogel reduced the resistivity of infarct tissue (MI vs PPy, 3.36 vs. 1.67KΩ. cm, P<0.01), improved electrical conduction(QT interval, 360.67 vs. 298.63ms, P<0.01), and rebalanced the cardiac autonomic nervous system(low frequency /high frequency, 1.03 vs. 0.51, P<0.01). PPy-chitin hydrogel improved left ventricular remodeling by improving myocardial fibrosis (11.42% vs. 7.56%, P<0.01) and promoting neovascularization. Ultimately, PPy-chitin hydrogel improved cardiac function at 4 weeks post-MI (left ventricular ejection fraction, 42.88% vs. 56.72%, P<0.01) and reduced post-MI arrhythmia susceptibility by 34.61%.

Conclusions:
Anisotropic conductive hydrogel significantly improved tissue remodeling, electrical remodeling and neural remodeling in the preclinical model of MI, further reducing the incidence of heart failure and ventricular arrhythmia after MI, which is expected to be translated into clinical practice.
Abstract 4142875: Beyond Static Cold storage: Partial freezing for extending heart preservation and improving recovery
Authors: Singh Gurjit , Al-attar Rasha , Lopera Higuita Manuela , Chen Maya , Pugeda Tyler , Uygun Korkut , Toner Mehmet , Tessier Shannon
Published: November 2024

Background:
Cardiovascular diseases, the leading cause of mortality with 17.9 million deaths annually (WHO), often necessitate heart transplants for end-stage organ failure. However, donor heart demand far exceeds supply. Traditional organ preservation methods like static cold storage (SCS) offer a limited 4-6 hour window, while machine perfusion (MP) extends this by circulating an oxygen-rich solution but faces challenges with nutrient depletion and metabolic imbalances. Our "partial freezing" method offers a novel approach to organ preservation using cryoprotectants (CPAs), by achieving a stable frozen state while maintaining an unfrozen fraction to limit ice damage and dehydration

Hypothesis:
Partial freezing (PF) method can effectively extend the storage duration of rodent hearts while maintaining their viability and function.

Methods:
The PF of the heart entails six major steps: (1) Procuring hearts (N=3) from adult male Lewis rats (2) Preloading of CPAs (DMSO, glycerol, raffinose, mannitol, and proline) during hypothermic Langendorff mode perfusion for 30 min (3) Freezing the hearts at a controlled rate of 0.3°C/min to -6°C (4) Storage at -6°C for 18 hours (5) Gradual thawing and unloading of CPAs (6) Recovery of hearts during NMP (normothermic machine perfusion) with antioxidant-supplemented Tyrode solution, followed by viability assessment using metabolic, hemodynamic, and molecular parameters. Two control groups were also included in the study: (1) Fresh hearts (N=3) functionally recovered in Tyrode solution, and (2) SCS hearts (N=3), perfused with cold University of Wisconsin (UW) solution and stored in the UW solution for 18 hours at 4°C, then recovered in same solution as the PF hearts.

Results:
NMP assessments revealed promising outcomes for PF hearts, with histology, TTC (Triphenyltetrazolium chloride) and Connexin-43 immunostaining profiles comparable to fresh controls and superior to SCS hearts. Although PF hearts exhibited lower beating rates, they demonstrated comparable metabolic parameters (lactate and oxygen consumption) and tissue edema compared to fresh controls, indicating preserved cardiac performance post-recovery.

Conclusion:
Our study shows the potential of the PF method to extend storage to 18 hours while maintaining viability and molecular function similar to fresh controls and superior to SCS hearts. This exploratory study suggests PF as a promising method to extend heart preservation times, addressing current limitations.
Abstract 4142919: Chronic administration of EDG-7500, a novel sarcomere modulator, prevents increases in cardiac mass, T1 relaxation time, and left ventricular end diastolic pressure in a Yucatan mini-pig model of genetic non-obstructive hypertrophic cardiomyopathy.
Authors: Emter Craig , Lehman Sarah , Lee Lindsey , DiNatale Emy , Peter Angela , Henze Marcus , Bluemke David , Tharp Darla , Roof Steve , del Rio Carlos , Semigran marc , Russell Alan , Evanchik Marc
Published: November 2024

Introduction:
Pathologic cardiac remodeling is a hallmark of hypertrophic cardiomyopathy (HCM). EDG-7500 is a novel oral, selective cardiac sarcomere modulator designed to slow the rate of contraction and speed the rate of relaxation without directly inhibiting myosin motor-head function. EDG-7500 is currently in a phase 2 clinical trial in HCM patients.

Aims:
To determine if EDG-7500 can prevent pathologic cardiac remodeling and disease progression in a mini-pig model of non-obstructive HCM (nHCM) caused by heterozygous
MYH7
R403Q mutation.

Approach:
R403Q pigs were assigned to 2 groups; placebo control (CTRL; n=7-11) and EDG-7500 treated for 5-6 months (n=5-9), with untreated wild-type (WT; n=6-11) as reference. Cardiac magnetic resonance imaging (CMR) and terminal tissue collection occurred at 7-8 months of age. CMR sequences were collected in 12-16 parallel, short-axis views using a 3T scanner for calculation of left ventricular (LV) EF, volumes, T1-time, and LV mass. LV and left atrial (LA) mass also were measured postmortem. LV end diastolic pressure (EDP) and the end diastolic pressure-volume relationship (EDPVR) were measured
in vivo
via catheter. Myocardial atrial and brain natriuretic peptide (ANP and BNP) mRNA and α and β myosin heavy chain (MYHC) proteins were evaluated. Statistical significance was set at P≤0.05 (*denotes vs. CTRL) using one way ANOVA or linear regression with data reported as mean±SE.

Results:
EDG-7500 prevented increases in LV mass both
in vivo
(CMR; *45±3 vs. 61±6 in CTRL; WT, 46±3g) and postmortem without affecting LV end diastolic volume and EF. EDG-7500 attenuated: 1) increased LV EDP (*10±1 vs. 25±3 in CTRL; WT, 8±1mmHg); 2) decreased LV compliance (EDPVR *1.6±0.2 vs. 3.9±0.4 in CTRL; WT, 1.0±0.1mmHg/mL); and 3) increased LA mass (*12±1 vs. 22±2 in CTRL; WT, 7±1g). EDG-7500 also prevented increased T1-time (*971±31 vs. 1107±26 in CTRL; WT, 925±33msec), which was positively correlated to LV EDP (R=0.75). EDG-7500 prevented HCM-mediated increases in LV BNP (*16±6 vs. 46±13 in CTRL; WT, 1±0.2) and LA ANP mRNA (*3±1 vs.15±4 in CTRL; WT, 1±3), while preventing a pathologic isoform shift to more LA β-MYHC protein (*89%α:11%β vs. 75%α:25%β in CTRL; WT, 92%α:8%β).

Conclusion:
In a mini-pig model of nHCM, chronic EDG-7500 therapy prevents pathologic cardiac remodeling, decreased LV compliance, and disease progression without impairing resting systolic function. These findings support clinical investigation of EDG-7500 in nHCM.
Abstract 4142930: Title: Loss of estrogen receptor α causes early onset of right ventricular capillary rarefaction in female rats with experimental pulmonary hypertension
Authors: Li Jiajun , Karoor Vijaya , Frump Andrea , Walts Avram , Lahm Tim
Published: November 2024

Background:
Right ventricular failure (RVF) determines survival in patients with pulmonary hypertension (PH). Insufficient angiogenesis and impaired RV endothelial cell (RVEC) function are key contributors of RVF development. Female patients with PH have better RV function compared to males. 17β-estradiol (E2), the most abundant female sex hormone, exerts RV-protective effects, including stimulation of angiogenesis. However, the mechanisms underlying E2’s pro-angiogenic function are unknown.

Hypothesis:
Estrogen receptor (ER)α promotes RVEC angiogenic function in vitro and RV angiogenesis in vivo.

Objective:
To identify the role of ERα in RVEC angiogenic function and RV angiogenesis.

Methods:
ERα loss-of-function mutant (ERα
Mut
) rats were generated using CRISPR-Cas9. RVF was induced in rats with monocrotaline (MCT; 60 mg/kg) or pulmonary artery banding (PAB; 11 weeks). RV systolic pressure (RVSP) was measured, and Fulton index and cardiomyocyte area were used as measures of RV hypertrophy. RV capillary density was assessed by Isolectin B4 staining. RVECs were isolated from male and female WT and ERα
Mut
rats. Cell migration was assessed using transwell migration assay. Angiogenic gene expression in RVECs was measured using Qiagen RT2 Profiler PCR array. p<0.05 by ANOVA or in Pearson’s correlation analyses was considered significant.

Results:
RV capillary loss was observed in male and female WT rats and female ERα
Mut
PAB rats, compared to sham (p<0.05). Capillary density correlated negatively with RVSP and Fulton index (p<0.001, r
2
=0.1386 and 0.4029, respectively). Time course experiments in MCT-rats demonstrated RV hypertrophy and capillary rarefaction in female ERα
Mut
rats (but not in WT) 10 days after MCT injection (p<0.05). Microarray indicated reduced expression of pro-angiogenic angiogenin and leptin and increased expression of anti-angiogenic TIMP-1 in female ERα
Mut
vs WT RVECs. Pathway analysis reaveled a decrease in mediators of cell migration and blood vessel development in ERα
Mut
vs WT RVECs. Transwell migration assay revealed reduced migration in male and female ERα
Mut
vs WTs RVECs at 24h (p<0.05).

Conclusions:
ERα regulates angiogenic processes in vivo and in RVECs in a sexually dimorphic manner. Functioning ERα protects females against capillary rarefaction during early stages of RV remodeling. Targeting ERα could pave the way for sex-specific treatment strategies aimed at bolstering RV adaptation in PH.
Abstract 4142950: Somebody Help! PulsePoint Directed Layperson CPR Response in Healthcare Adjacent Facilities
Authors: Sedor-Schiffhauer Zachary , Lane Nina , Xiong Jonathan , Gutta Gnanesh , Weiss Leonard , Doshi Ankur , Salcido David
Published: November 2024

Introduction:
Cardiac arrest is an emergency that requires action via timely administration of CPR and AED use. PulsePoint is a phone application that alerts layperson users of nearby cardiac arrest events allowing them to provide aid before first responders arrive. Hospitals already have cardiac arrest protocols and are therefore excluded from PulsePoint. However, healthcare adjacent facilities (HAFS), locations that provide medical services without being inpatient treatment centers, may or may not have cardiac arrest protocols. It is unknown whether PulsePoint layperson dispatch to HAFS would be beneficial for CPR response or AED retrieval.

Hypothesis:
HAFS already have internal cardiac arrest response protocols. The same facilities can make AEDs available in nearby areas.

Goal:
Categorize HAFS related to cardiac arrest response or AED retrieval for PulsePoint alerts.

Methods:
We retrieved 940 records from the Allegheny County, PA PulsePoint deployment from 2022-2023, including only events occurring in public locations classified as HAFS. Health care adjacency was manually determined by a single reviewer, using a primary criterion of providing health care services but excluding inpatient facilities. The team contacted each site via telephone to administer a standardized survey querying the facility’s cardiac arrest response procedure, presence of an AED, and whether PulsePoint responders could enter their facility in response to an emergency.

Results:
Of the 108 HAFS identified, 46 (42.6%) completed the phone survey and 44/46 (95.7%) have a cardiac arrest response protocol. Additionally, 39/46 (84.8%) of facilities have an AED on-site and 100% of those facilities have staff present who are trained in AED use. A total of 5/46 (10.9%) facilities were aware of or had staff who were aware of PulsePoint. Permission for PulsePoint responders to enter their facility 9/46 (19.6%) was low, but AED use in the nearby community was higher at 25/46 (54.3%).

Conclusion:
The majority of HAFS have existing cardiac arrest protocols and AEDs available. Dispatch of PulsePoint volunteers to HAFS may be inefficient, however, willingness to provide AEDs suggests that HAFS could play a supportive role to bystander cardiac arrest response. Future steps would best focus on exploring means to overcome low survey participation to properly characterize response protocols, investigating individualized location designation within PulsePoint, and increasing knowledge of PulsePoint.
Abstract 4142999: How many and which leads in ECG do you need to estimate a patient’s ejection fraction? A Deep Learning Approach.
Authors: Ku Tienhsiung , Chang Hao-Chun , Chiu Chih-Wei , Shih Dann-Pyng , Li Tzong-shiun , Tsai Ming-Tse
Published: November 2024

Patients with heart failure (HF) can range from being asymptomatic to experiencing various combinations of symptoms. Left ventricular ejection fraction (EF), measured via echocardiography, is the primary tool to differentiate between different HF types and guide therapies. However, the availability of echocardiography varies geographically. In contrast, electrocardiograms (ECGs) are more common and easily accessible. In this study, we use a deep learning approach to correlate ECG readings with their corresponding EF. Low EF is defined as ≤ 35%.

Patients with the International Classification of Diseases codes for HF were screened retrospectively at Changhua Christian Hospital, Taiwan, from 2016 to 2022 with IRB approval. Only data comprising sex, age, a 10-second ECG record with a sampling rate of 500 Hz, and an echocardiography report obtained within 7 days after ECG acquisition were included. There were 3,508 samples (low EF: normal EF = 1,430:2,078) from 1,240 patients in the dataset. We reserved 10% of the samples as the final testing set (n=351) and split the remaining 90% randomly into the training and validation sets (n=2,525 and n=632) in a ratio of 8:2. A convolutional neural network was trained to classify input ECG lead(s) as either low or normal EF. For simplicity, the model with the lowest validation loss was selected and further evaluated on the final testing set.

There were 721 males and 519 females with a mean age of 70.47 (±14.59). We experimented with various combinations of limb and chest leads as input ECG data and used the validation set to assess their performance, as shown in Table 1. The model trained with leads V2, I, and II had the lowest validation loss and achieved 71.3% sensitivity, 88.6% specificity, and an AUC of 87.6% on the testing set.

With more information from multiple leads, a patient’s EF could be better predicted; however, the incremental benefits tapered off quickly. In our investigation, the best model was found by combining information from three leads: I, II, and V2. Our study discovered a pathway to ECG-based artificial intelligence applications and provided innovative insights into medical device design, which could benefit patients in under-resourced areas.
Abstract 4143001: Rapid Diuresis Protocol in Decompensated Heart Failure: Improving Guideline-Directed Medical Therapy Titration and Timely Outpatient Follow-up
Authors: Munoz Sherilyn , Habhab Mazin , Hollowell Matthew , Weber Paul , Crane Ryan , Bury Anastasia , Korn Morgan , Mitchell Nicole , gonzalez matthew
Published: November 2024

Current guidelines for treating acute decompensated heart failure (ADHF) recommend inpatient intravenous diuresis until congestion relief, as well as the initiation and advancement of guideline-directed medical therapy (GDMT). Our institution has developed a rapid diuresis team (RDT) to expedite decongestion in hospitalized ADHF patients with the goal of safely reducing length of stay. This study examines the RDT’s potential impact on GDMT titration as well as outpatient follow up timing.

Does the RDT protocol improve GDMT titration and time to outpatient follow-up after discharge in patients with ADHF?

This retrospective single-center study includes patients undergoing inpatient treatment for ADHF from March 2022 to November 2023 at a tertiary referral center. Demographic, clinical, and laboratory data were obtained. Standard parametric and non-parametric analyses were conducted, along with Kaplan-Meier curve analysis, with statistical significance set at p<0.05. The RDT protocol involves early aggressive diuresis with daily monitoring of weight, fluid intake, and urine output. Aggressive diuresis goals (3-4 L/day urine output) were set and included regular assessments by a multidisciplinary team. Discharge criteria focus on resting symptom resolution, adequate oral diuretic response, and an established follow-up within 3-5 days where GDMT can be adjusted as needed.

Out of 255 patients, 128 underwent RDT and 127 received standard care. Patients in the RDT protocol had a shorter average time from hospital discharge to cardiology appointment (4 days vs. 5 days; p = 0.044). Additionally, those in the RDT protocol tended to have higher rates of follow-up within 30 days post-discharge (90% vs. 77%; p = 0.052) (Figure 1). GDMT titration prior to discharge was more common in the RDT group (93 vs. 74 patients; p = 0.025). At the follow-up visit, GDMT titration was also more frequent in the RDT group (55 vs. 43 patients; p = 0.207).

Compared to standard care, the RDT protocol results in a shorter time to outpatient follow-up and improved inpatient and outpatient GDMT titration for the treatment of heart failure. The implementation of the RDT protocol appears to enhance the management and outcomes of patients with ADHF.
Abstract 4143074: Left Atrial Stiffness in Patients with Cryptogenic Ischemic Stroke
Authors: Hernandez del Rio Jorge Eduardo , Miranda - Aquino Tomas , Gonzalez-Padilla Christian , Lomeli Sanchez Oscar , Ochoa Castillo Daniel , Alonso Diaz Daniela Alejandra , Gloria Valencia Natalia
Published: November 2024

Introduction:
Atrial fibrillation (AF) is a risk factor for the development of ischemic stroke. Left atrial (LA) function has been described as a predictor of AF, however, atrial stiffness has been little studied.

Objectives:
To determine if there is a difference in left atrial stiffness between patients with ischemic stroke who presented AF and those who did not, the association of stiffness with AF and the stiffness cut-off points.

Methods:
An analytical, cross-sectional, single-center study was conducted. Patients older than 18 years with a diagnosis of cryptogenic ischemic stroke who were in sinus rhythm, had no history of atrial fibrillation and underwent an echocardiogram and a 24-hour rhythm Holter during hospitalization were included in the study.

The echocardiograms were performed using a Siemens ACUSON SC 2000 machine with a 2.5 MHz sectorial 4v1c transducer. The reservoir LA strain (LASr) was determined using the VVI technique. The left atrial stiffness was obtained through the ratio E/e’ between the LASr.

Variables were analyzed using chi-square or Student's t-test. ROC curves were used to determine the cutoff points for predicting AF. The association of variables with the development of AF was analyzed using logistic regression.

Results:
A total of 96 patients were obtained, of which 35 had documented AF, 16 women and 19 men. Two groups were formed, Group 1: patients with ischemic stroke and AF (35), Group 2: with ischemic stroke without AF (61), which were used as control (Table 1). Among patients with AF, we found they were older and had a higher prevalence of diabetes mellitus, higher E/e' value, LA indexed volume, and greater LA stiffness as well as lower LASr values. LA stiffness (>0.29) and LASr (<36%) were the best predictors of AF in the ROC curves (Image 1) . The association with the development of AF found that LA stiffness was significant in both univariate and multivariate analyses (Table 2).

Conclusion:
The stiffness of the left atrium is an easy-to-determine echocardiographic parameter that allows us to predict the presence of atrial fibrillation in patients with an ischemic cerebrovascular event who should have a greater intentional search for atrial fibrillation.
Abstract 4143101: Cardiotoxicity of Anthracycline and Pembrolizumab Compared to Anthracycline Alone in Management of Triple-Negative Breast Cancer: A Retrospective Cohort Study
Authors: Holley Nolan , Monroe Gary , Gallagher Micheal , Ahmad Syed , Inderbitzin-Fischer Sonya , Hartzell Michelle , Tella Pranathi , Batool Izza , Hill Jordan , Kurian Sobha , Patel Brijesh
Published: November 2024

Introduction:
In a major paradigm shift of management of high-risk early-stage triple negative breast cancer (TNBC), the KEYNOTE-522 trial showed evidence to suggest that the addition of the immune checkpoint inhibitor (ICI) pembrolizumab to current standard-of-care chemotherapy leads to greater clinical efficacy than that of chemotherapy alone. However, the addition of an ICI carries with it the risk of immunotherapy-related cardiotoxicities. This raises concern for additive risks for cardiotoxicity for patients with high-risk early-stage TNBC receiving both anthracycline and ICI.

Hypothesis:
Management of high-risk early-stage TNBC with a treatment regimen consisting of anthracycline and ICI will have no increase in cardiotoxicity when compared to those receiving anthracycline alone.

Aims:
The purpose of this study is to identify if the combination of anthracycline and ICI in the management of high-risk early-stage TNBC is associated with greater cardiotoxicity than that of those on anthracycline alone.

Methods:
Patients with TNBC were identified within the electronic health record system at our institution. Cohorts were created based on management strategy: anthracycline with ICI and anthracycline without ICI. Patient demographics, comorbidities, functional status, medications, cardiac imaging, management, and outcomes were analyzed retrospectively. Cohorts were then compared for analysis of time to adverse cardiac event. An alpha value of 0.05 was used to determine statistical significance.

Results:
A total of 385 patients with TNBC were included in the study, with 312 receiving anthracycline without ICI and 73 receiving anthracycline with ICI. Baseline characteristics between the two cohorts were well balanced with no significant differences in prevalence of comorbidities. There were no significant differences in incidence of general cardiac events, heart failure, acute coronary syndrome, cardiac arrhythmias, and pericardial effusion between these two cohorts following each respective treatment regimen. Furthermore, there was no significant difference in time to cardiac events between the two groups.

Conclusion:
There appears to be no significant differences in cardiac events between patients with TNBC on anthracycline with ICI and those on anthracycline without ICI. Given no significant differences in cardiotoxicity, these findings further favor use of an ICI in management of high-risk early-stage TNBC and serve to reduce clinician hesitancy.
Abstract 4143118: Association of Left Atrial Fibrosis with AF Burden Post-Ablation: Insights from the DECAAF II Study
Authors: Younes Hadi , Mahnkopf Christian , Noujaim Charbel , bidaoui ghassan , Bsoul Mayana , Feng Han , El Hajjar Abdel Hadi , Mekhael Mario , Dagher Lilas , Lim Chanho , Rao Swati , Tirado Polo Francisco , Liu Yingshuo , Jia Yishi , Tsakiris Eli , Assaf Ala' , Ademi Besim , Shamaileh Ghaith , Hui Yanpei , donnellan eoin , Pandey Amitabh , Marrouche Nassir
Published: November 2024

Introduction:
Left atrial (LA) fibrosis identified by delayed enhancement MRI has been linked to poor outcomes post-AF ablation. We aim to assess the relationship between LA fibrosis and post-ablation AF burden in a persistent AF population.

Methods:
This is a subanalysis from the DECAAF II trial which included persistent AF undergoing catheter ablation. Delayed enhancement MRI was performed up to 30 days pre-ablation. Fibrosis was quantified at a core lab and categorized into 4 stages: 1 (<10%), 2 (10%-<20%), 3 (20%-<30%), and 4 (≥30%). AF burden was defined as the percentage of time in AF post-ablation and was monitored using a 1-lead EKG device.

Results:
This analysis included 658 patients. After ablation, patients were followed, categorized by Utah stage as follows: 95 in stage I, 380 in stage II, 271 in stage III, and 69 in stage IV. The mean (SD) AF burden during the blanking period (0 to 3 months) was 0.15 (0.26) for stage I, 0.17 (0.26) for stage II, 0.22 (0.29) for stage III, and 0.29 (0.30) for stage IV (p<0.001). Post-blanking period (after 3 months), the mean (SD) AF burden was 0.13 (0.22) for stage I, 0.15 (0.21) for stage II, 0.19 (0.25) for stage III, and 0.27 (0.27) for stage IV (p<0.001).

Conclusion:
A higher atrial fibrosis identified by delayed enhancement MRI was associated with increased AF burden post-ablation.