bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract We107: Reduction of Six-Month Heart Failure Readmission Rates in Patients Undergoing MitraClip with Beta Receptor Blockade
Authors: Najam Usman , Iskander Joseph , Avino Timothy , Drago Thomas , Deonaraine Kristina , Pasha Arham
Published: October 2024

Introduction:
MitraClip has been shown to reduce heart failure readmissions in patients with moderate to severe mitral valve regurgitation. Likewise, beta-blocker (BB) therapy has been shown to reduce morbidity and mortality in select heart failure patients. At the cellular level, chronic myocardial insult from ongoing heart failure and mitral regurgitation leads to persistent overstimulation of myocardial beta-receptors, ultimately reducing cardiac inotropic reserve and contributing to myocardial injury. Thus, we hypothesized that patients on beta-blocker therapy before the MitraClip procedure would have fewer heart failure-related readmissions.

Hypothesis:
We assessed the hypothesis that beta-blocker therapy before the MitraClip procedure would lead to fewer heart failure-related readmissions by conducting a retrospective cohort study. This would help us better understand the pathogenesis of re-admissions in this patient population as well as help us decide whether prophylactic initiation of BB therapy before the procedure would reduce the risk of heart failure readmissions.

Methods:
We reviewed the records of patients who underwent the MitraClip procedure at our institution from January 2017 to July 2022. Patients without listed home medications, as well as non-heart failure-related readmissions and deaths, were excluded. Patients were split into those on BB therapy and those with no BB therapy. Of the 401 charts screened, 324 met the inclusion criteria.

Results:
From those who met the inclusion criteria, 226 patients were on beta-blocker therapy, while 98 patients were not. Of those who had at least one heart failure-related readmission within 6 months of the MitraClip procedure, 18 patients were on beta-blocker therapy and 16 patients were not. Meaning a 7.96% readmission rate for patients on beta-blocker therapy, and a 16.32% readmission rate for those who were not (OR 2.05, 95% CI: 1.004 to 4.186, p<0.05), with the number needed to treat being 11.9.

Conclusions:
Our data shows that the use of beta-blocker therapy was associated with a statistically significant decrease in 6-month heart failure readmissions in those undergoing the MitraClip procedure. This suggests that at the cellular level, cardiac beta receptor dysfunction plays an integral part in future hospitalizations in this population. In conclusion, beta-blocker therapy should be considered in heart failure patients planning to undergo the MitraClip procedure to reduce heart failure-related readmissions.
Abstract We108: Adipocyte Enhancer Binding Protein 1 (AEBP1) Inhibition as a Potential Anti-Fibrotic Therapy in Heart Failure
Authors: Shankar Thirupura S , Visker Joseph , Amrute Junedh , Polishchuk Georgiy , Lunde J Ty , LING JING , Ferrin Peter , Hamouche Rana , Feigle Dominik , Calder Dallen , Sachse Frank , Kyriakopoulos Christos , Maneta Eleni , Srinivasan Harini , TSELIOU ELENI , Navankasattusas Sutip , Selzman Craig , Boudina Sihem , Seidel Thomas , Lavine Kory , Drakos Stavros
Published: October 2024

Introduction:
Cardiac fibrosis is one of the major hallmarks of heart failure (HF) progression. Fibrosis is initiated as a repair mechanism following any kind of cardiac injury including a heart attack, inflammation, hypertension, etc. Briefly, fibroblasts are activated to form myofibroblasts that secrete collagen. Persistent fibroblast activation leads to excess collagen deposition leading to tissue stiffening and impaired contractility and thereby HF. To date, there is no anti-fibrotic therapy used in HF patients.

Using bulk and snRNA sequencing data performed on myocardial tissue from HF patients, we identified adipocyte enhancer binding protein (AEBP1) to be significantly upregulated in activated fibroblasts. AEBP1 has been shown to play a crucial role in fibroblast activation following injury in the kidney, liver, and lungs. AEBP1 inhibition resulted in fibrosis attenuation in these organs. However, its role in cardiac fibrosis is not well understood.

Hypothesis:
We hypothesize that AEBP1 is crucial for cardiac fibroblast activation and AEBP1 inhibition will prevent collagen secretion and lead to improved cardiac function.

Methods:
Human cardiac fibroblasts (HCF) from non-failing donors were used for in vitro experiments. AdV-CMV-AEBP1 was used for AEBP1 overexpression (OE) and AdV-CMV-shAEBP1 was used to knockdown (KD) AEBP1 in vitro. AAV9-CMV-shAEBP1 was used for in vivo KD of AEBP1 in mice following myocardial infarction (MI). Human myocardial slices from n=6 HF patients were used and AdV-CMV-shAEBP1 was used to knockdown AEBP1 in human samples.

Results and Discussion:
AEBP1 OE in HCF resulted in fibroblast activation and collagen secretion (n=6, p=0.002). Contrarily, loss of AEBP1 significantly prevented fibroblast activation, evident from a reduction in transgelin (SM22) (n=6, p=0.02) and collagen (COL1A1) protein levels (n=6, p=0.01). AEBP1 KD in a mouse model of acute cardiac fibrosis resulted in reduced fibrosis and improved cardiac function (n=6, 12% absolute improvement compared to untreated mice, relative improvement in ejection fraction, p=0.02). Tissue culture studies of human HF myocardium showed a significant improvement in cardiac structure evident from reduced cardiomyocyte hypertrophy (n=6 HF patients, p=0.05) and reduced fibrosis (n=6, p<0.0001) following AEBP1 KD. Overall, we show that AEBP1 plays a critical role in fibrogenesis, and its inhibition has the potential to attenuate fibrosis in acute and chronic HF.
Abstract We110: Novel allosteric ligand designed to prevent Autoantibody targeting the Angiotensin Type 1 Receptor (AT1R) in cardiovascular diseases (CVD)
Authors: Khuraijam Dhanachandra Singh , Pardhi Triveni , Harford Terri , Ravu Tarun , Desnoyer Russell , Mohan Maradumane , Liu Chia-Feng , Naga Prasad Sathyamangla , Tang Wai Hong , Karnik Sadashiva
Published: October 2024

Background:
The clinical data suggest an association of autoantibodies (AAb) targeting angiotensin II type1 receptor (AT1R) and outcomes in heart failure (HF) and preeclampsia. Notably, patient’s risk increases 2 to 4-fold for heart diseases and hypertension. Although AT1R blockers (ARBs) have emerged as a key component in the therapeutic arsenal against CVD, we believe that rather than completely blocking AT1R signaling, maintaining a balanced signaling is crucial for cardiovascular homeostasis. Therefore, we posit that reducing AT1R overactivation and blocking AAb-mediated activation could benefit cardiac health and attenuate the progression of CVD. In our previous study (PMID:36440576), we identified small molecules capable of inhibiting AAb-induced AT1R signaling. Leveraging these observations, we have developed a novel AT1R allosteric ligand that inhibits autoantibody binding to AT1R while still retaining normal AT1R signaling.

Methods:
Using computational and medicinal chemistry approaches, we designed a series of novel AT1R ligands and obtained compounds with >98% purity through chemical synthesis. Monoclonal antibodies mimicking AT1R-AAb have been generated. Serum samples from dilated cardiomyopathy (DCM) and preeclampsia (PE) patient cohorts were collected and presence of AT1R-AAb was determined using ELISA and epitope-peptide competition studies. Pharmacological characterization of compounds was performed using calcium mobilization,
125I
-AngII binding,
ex vivo
vasoconstriction, and ELISA assays.

Results:
We identified an AT1R allosteric compound that reduced AngII-mediated calcium signaling with a 5-fold shift in EC
50
. The IC
50
was determined to be 18 µM. It reduces the AngII-mediated vasoconstriction while blocking both monoclonal and patient-derived autoantibody binding with an IC
50
of 5 µM.

Conclusion:
We have identified a novel AT1R allosteric ligand with negative allosteric modulator (NAM) properties, which has the potential to block autoantibodies and could serve as a new generation of ARBs. Uniquely, it retains beneficial AT1R signaling without competing with AngII, and its allosteric ligand property can be tailored to achieve optimal AT1R signaling.
Abstract We112: Volumetric imaging to recapitulate cardiac injury and arrhythmias
Authors: Ding Yichen , Saberigarakani Alireza , Zhang Xinyuan , Almasian Milad , Yuan Jie
Published: October 2024

Advanced understanding of cardiac structure and function is crucial for uncovering the underlying mechanism of injury and arrhythmias. To explore cues to structural and functional abnormalities in extensively established animal models, we have developed optical imaging and computational methods tailored to investigate intact hearts of zebrafish and rodents at cellular resolution. Our cardiac light-field microscopy allows us to capture instantaneous dynamics such as calcium transients, irregular contraction, and blood flow at 200 volumes per second in zebrafish larvae
1
. To improve the spatial resolution and enable the study of rodent models, we have customized two light-sheet imaging systems. One system is empowered by the retrospective synchronization and machine learning for the study of contractile function and focal myocardial mechanics from end-systole to end-diastole
2
, while the other integrates tissue clearing and axially scanning approaches for the exploration of ventricular trabeculation and myocardial compaction
3
. These methods aim to overcome the trade-off in spatial resolution, imaging speed, field of view across the atria and ventricles with minimal photo-damage and maximal penetration depth, enabling long-term investigation of cardiac development and regenerative processes. To further interpret the large volume of datasets, we have customized a successive subspace learning and virtual reality-based platform for interactive image analysis
4
. Collectively, our multi-scale strategy has opened up new landscapes for exploring the cardiac micro-structure and contractile function, both in health and disease.

References

1. Saberigarakani A, et al. Light-field microscopy to study cardiac arrhythmias in zebrafish larvae. In: Three-Dimensional and Multidimensional Microscopy: Image Acquisition and Processing XXXI. 2024. p. 48–55.

2. Zhang X, et al. 4D Light-sheet imaging and interactive analysis of cardiac contractility in zebrafish larvae.
APL Bioeng
. 2023;7:26112.

3. Almasian M, et al. 3D isotropic light-sheet imaging to reveal the structure of neonatal mouse hearts. In: Three-Dimensional and Multidimensional Microscopy: Image Acquisition and Processing XXXI. 2024. p. PC128480F.

4. Yuan J, et al. Extended reality for biomedicine.
Nat Rev Methods Prim
. 2023;3:14.
Abstract We113: Intravascular Theranostic Photoactivation Guided By OCT-NIRF Dual-Modal Imaging Facilitates Inflammation Resolution of High-Risk Plaque
Authors: Kim Jin Hyuk , Kim Yeon Hoon , Kim Hyun Jung , Kim Ryeong Hyun , Park Ye Hee , Nam Hyeong Soo , Kang Dong Oh , Yoo Hongki , Park Kyeongsoon , Kim Jin Won
Published: October 2024

Introduction and Hypothesis:
Photoactivation eliminates inflammatory cells and promotes healing, paving the way for atherosclerosis intervention. We hypothesized that intravascular macrophage-targeted near-infrared fluorescence (NIRF) emitting photoactivation could facilitate inflammation resolution and stabilize the inflamed high-risk plaques.

Method and Results:
We newly fabricated a Dectin-1-targeted photoactivatable theranostic agent through the chemical conjugation of the NIRF-emitting photosensitizer chlorin e6 (Ce6) and the Dectin-1 ligand laminarin (LAM-Ce6). By intravascular OCT-NIRF structural-molecular imaging at 0- vs 4 weeks, LAM-Ce6 under light irradiation through a customized intravascular fiber effectively attenuated inflammatory NIRF signals, resulting in replacement of fibrotic composition in the targeted plaques (Figure A,
P
<0.01). Mechanistically, one hour after the light irradiation, autophagy was strongly augmented with the formation of autophagolysosomes (Figure B,
P
<0.001) and an increase of CD206-positive cells at 7 days. Furthermore, TUNEL/RAM11- and CD206/MerTK-positive cells were prominently increased at 1 day, suggestive of enhanced efferocytosis in the treated plaques (Figure C, the white arrow: macrophage associated apoptotic cells,
P
<0.05). In line with inflammation resolution, photoactivation enhanced the cholesterol efflux regulatory protein ABCA1 and induced TGF-β in macrophages, which subsequently stimulated smooth muscle cells and produced collagen within the lesions (Figure D).

Conclusions:
The macrophage Dectin-1 targetable intravascular photoactivation assisted by OCT-NIRF catheter imaging could ultimately transit the plaque phenotype to collagen-rich fibrotic one by autophagy-mediated inflammation resolution with a fibrotic replacement. This novel targeted photoactivation is expected to offer new opportunity for the catheter-based theranostic strategy in patients with macrophage/lipid-rich inflamed coronary plaques.
Abstract We118: Phosphoglycerate Dehydrogenase Gene Therapy for Dilated Cardiomyopathy
Authors: Kay Maryam , Apel Anne-Maj , Bharucha Nike , Baum Rachel , Li Xueyi , Laguerre Aurelie , Metallo Christian , Kapiloff Michael , Karakikes Ioannis
Published: October 2024

Introduction:
Dilated cardiomyopathy (DCM) is a multifaceted cardiac disorder affecting approximately 1 in 250 to 2000 individuals and stands as a predominant cause of heart failure. Despite advancements in identifying genetic mutations associated with DCM, the precise mechanisms driving its pathogenesis are unknown, translating to the lack of disease-modifying interventions.

Hypothesis:
Modulating serine biosynthesis and one-carbon metabolism in cardiomyocytes by forced expression of Phosphoglycerate Dehydrogenase
(
PHGDH) will ameliorate cardiac dysfunction in DCM and halt the disease progression.

Methods:
We developed a gene therapy vector expressing the
PHGDH
gene, controlled by a chicken cardiac-specific promoter (cardiac troponin T, cTnT) (AAV9.cTnT.hPHGDH). We delivered this construct via an AAV-based gene transfer approach using the cardiotropic adeno-associated virus serotype-9 in the TM54 DCM mouse – a well-established transgenic mouse that expresses a mutant tropomyosin cDNA (Tpm1 p. E54K; Tm54) under the control of the cardiac αMHC promoter. At 6 weeks old, when the animals exhibit DCM, they were treated with AAV9.cTnT.hPHGDH or control (AAV9.cTnT.GFP). Serial echocardiography was employed to assess heart function for 10 weeks. Morphometric data including heart weight, body weight, and tibia length were recorded. Subsequently, WGA and picrosirius red staining were performed to evaluate cardiomyocyte size and fibrosis, respectively. Finally, metabolic changes were assessed by untargeted metabolomics.

Results:
AAV9.cTnT.hPHGDH treatment of DCM TM54 mice improved the systolic function and halted the progression of DCM compared to the control mice. Furthermore, PHGDH treatment prevented the development of interstitial fibrosis and cardiomyocyte hypertrophy. Finally, these functional and structural improvements correlate with metabolic rewiring of the glucose metabolism in the DCM heart.

Conclusion:
These findings suggest that metabolic rewiring of the glucose metabolism by enhancing serine biosynthesis and one-carbon metabolism in the DCM heart may be cardioprotective. Thus, PHGDH gene therapy may be a novel therapeutic approach for DCM and heart failure.
Abstract We120: NHE1 Regulates Apoptosis Susceptibility in Sugen-Hypoxia Pulmonary Arterial Smooth Muscle Cells via Modulation of CHOP
Authors: Ribas Andrade Manuella , Yun Xin , Shimoda Larissa
Published: October 2024

Pulmonary hypertension (PH) is caused by lung vascular remodeling involving increased pulmonary arterial smooth muscle cell (PASMC) proliferation and apoptosis resistance. Na
+/
H
+
exchanger (NHE) isoform 1 (NHE1) is a membrane protein regulating intracellular pH (pH
i
) via movement of H
+
. Our lab found increased NHE activity is associated with hyperproliferation in PASMCs from the Sugen Hypoxia (SuHx) animal model of PH. In this study, we tested the
hypothesis
that increased NHE1 activity also causes apoptosis resistance in SuHx PASMCs via dysregulation of pH
i
.

PASMCs isolated from distal pulmonary arteries of control and SuHx rats were treated with NHE inhibitor, [5-(N-ethyl-N-isopropyl)-amiloride; EIPA;1 uM], NHE1 inhibitor [cariporide;10 uM] or vehicle for 24 h before analyzing cell apoptosis via Hoechst staining under baseline and stimulated (250 uM H
2
O
2
) conditions. Control PASMCs were infected with adenovirus containing green fluorescent protein (GFP), wild-type NHE1 (WT) or NHE1 lacking ion translocation activity (E262I). Protein expression and localization were assessed via immunoblotting. NHE activity was assessed from Na
+
-dependent recovery following an ammonium pulse.

At baseline, apoptosis in SuHx PASMCs was similar to control cells but following H
2
O
2
stimulation
,
SuHx PASMCs were resistant to apoptosis (p<0.001). EIPA increased basal and stimulated apoptosis in SuHx cells. Surprisingly, treatment with cariporide did not alter SuHx apoptosis, suggesting that EIPA but not cariporide was able to sensitize SuHx cells to apoptosis, despite both drugs significantly inhibiting NHE activity, suggesting EIPA affects PASMC apoptosis through a mechanism other than pH
i
regulation. To test this possibility, control PASMCs were infected with GFP, WT or E262I. NHE activity was increased in cells with WT, but not E262I, when compared to GFP (p<0.001). Overexpression of either WT or E262I inhibited apoptosis following treatment with H2O2 (p<0.001). We next explored CAAT/enhancer binding protein homologous transcription factor (CHOP), known to be involved in induction of apoptosis. CHOP expression was increased by H2O2 in control cells but was decreased in SuHx PASMCs. EIPA increased CHOP levels in SuHx cells, whereas, expression of both WT and E262I constructs inhibited the H
2
O
2
-induced CHOP increase in control PASMCs.

Our results indicate that NHE1 regulates apoptosis susceptibility in PASMCs during PH via modulation of CHOP rather than through pH
i
regulation.
Abstract We121: Doxorubicin-Induced Cardiomyocyte Death is mediated by Lysosomal Membrane Permeabilization
Authors: Nasef Demarcus , Nasef Daniel , Hahn Younghee , Kobayashi Tamayo , Huang Yuan , Stout Randy , Liang Qiangrong , Kobayashi Satoru
Published: October 2024

Doxorubicin (DOX) is a potent antineoplastic drug with broad-spectrum capabilities. However, its clinical use is hindered by dose-dependent cardiotoxicity, often leading to heart failure. This study investigates the connection between DOX-induced cardiotoxicity and lysosomal dysfunction, focusing on lysosomal membrane permeabilization (LMP) as a central mechanism in cardiomyocyte death. LMP occurs when there is a disruption in the integrity of the lysosomal membrane, releasing lysosomal enzymes into the cytoplasm. We tested the hypothesis that DOX induces LMP, contributing to cardiomyocyte death.

Utilizing a tfGalectin3 LMP reporter and Lysosensor staining, we verified LMP occurrence in DOX-treated H9C2 cardiomyoblast cells, as indicated by compromised lysosomal acidity and increased release of lysosomal protease Cathepsin D (CTSD). Western blot analysis showed elevated CTSD expression following DOX exposure, while DQRed BSA staining demonstrated diminished lysosomal proteolysis, signifying lysosomal dysfunction. Intriguingly, downregulating CTSD via siRNA aggravates cardiomyocyte death, whereas enhancing CTSD expression through adenoviral delivery exerts opposite effects, suggesting a protective role of CTSD in DOX cardiotoxicity. In vivo study using a tfGalectin3 LMP reporter mouse validated the ability of DOX to induce LMP in cardiac tissue. CTSD heterozygous knockout mice exhibited deteriorated heart function compared to the wild type, underscoring CTSD's protective role against DOX-induced cardiotoxicity. In summary, our findings highlight the critical impact of DOX on lysosomal stability and protease activity, leading to cardiomyocyte death and cardiac dysfunction. Further studies are warranted to explore potential interventions, such as imidazolines and apolipoproteins, to reinforce LMP stability and safeguard against DOX-induced cardiotoxicity.
Abstract We122: Suppression of defender against cell death 1 (Dad1) induces cardiomyocyte death by regulating cell adhesion proteins.
Authors: Mori Shota , Tanaka Shota , Okada Yoshiaki , Obana Masanori , Fujio Yasushi
Published: October 2024

Introduction:
Suppression of cardiomyocyte loss is considered a promising strategy for the prevention of the onset of heart failure (HF). Previously,
defender against cell death 1
(
Dad1
) was identified as a cytoprotective gene. Dad1 forms a complex with staurosporine and temperature sensitive 3A (Stt3A), a catalytic subunit of oligosaccharyltransferase (OST) complex which is responsible for N-glycosylation. However, the function of Dad1 in cardiomyocytes remains unknown.

Hypothesis:
The disruption of cell-extracellular matrix interactions results in cell death, known as anoikis. Because various cell adhesion proteins are N-glycosylated, we hypothesized that Dad1 suppressed anoikis by regulating N-glycosylation of cell adhesion proteins in cardiomyocytes.

Methods:
Neonatal rat cardiomyocytes were cultured and the expression of Dad1 or Stt3A was knocked down using siRNA. The protein expression was assessed with immunoblot analysis, and cell viability was evaluated using a CellTiter-Blue assay kit.

Results:
The suppression of Dad1 using siRNAs reduced cardiomyocyte viability (
p
<0.01, n=4). Interestingly, suppression of Dad1 impaired the N-glycosylation of integrin β1 and decreased the expression of mature integrin β1 (
p
<0.01, n=3). These changes inactivated integrin-mediated signal transduction through dephosphorylation of focal adhesion kinase (
p
<0.01, n=5). In addition, enhanced cell-extracellular matrix interactions by using adhesamine rescued the cardiomyocyte death by Dad1 knockdown (
p
<0.01, n=4). Next, we pursued the relationship between Dad1 and Stt3A. Dad1 knockdown decreased the expression of Stt3A (
p
<0.01, n=6). Suppression of Stt3A induced cardiomyocyte death accompanied by the changes of cell adhesion proteins (
p
<0.01, n=4). Finally, double knockdown of Dad1 and Stt3A did not induce a further reduction in cell viability compared with the knockdown of only Dad1 (
p
<0.05, n=4), suggesting that cardiomyocyte death by Dad1 knockdown was dependent on Stt3A.

Conclusion:
Dad1 is required for the stabilization of Stt3A and suppresses cardiomyocyte anoikis by regulating N-glycosylation of cell adhesion proteins in an OST-dependent manner. Dad1-mediated cardiomyocyte survival could be a therapeutic target against HF.
Abstract We132: Genetic Blockade of PKA-mediated Phosphoregulation of 26S Proteasomes Exacerbates Pathology in Both the Brain and Heart of an Alzheimer’s Disease Model
Authors: Ejaz Saima , Sternburg Jack , Wang Hongmin , Khosrow Rezvani , Wang Xuejun
Published: October 2024

Background:
Alzheimer’s disease (AD) patients often display not only cognitive impairment but also cardiac malfunction, but the underlying factors remain elusive. Phosphorylation of Ser14 of RPN6 (p-S14-RPN6) is required for cAMP/protein kinase A (PKA) to activate 26S proteasomes. Proteasome priming is implicated in the protection by cAMP-PKA augmentation against AD, but this remains to be established. Hence, we conducted this study to address these critical gaps.

Methods:
The Rpn6
S14A
knock-in mice recently created for genetic blockade of p-S14-Rpn6 were crossbred with the PS19 tauopathy model (Jackson Lab Stock # 008169). Littermate wild type (WT), PS19, and PS19::S14A mice were compared. Cardiac function was evaluated with echocardiography (Echo). Hippocampal and myocardial tissues were used for western blot analyses (WB) and histopathology.

Results:
Increases in hippocampal insoluble tau proteins and in total and K48-linked ubiquitin conjugates were markedly greater in PS19::S14A mice than PS19 and WT mice. WBs for PSD95, synaptotagmin, Neu N, GFAP, and IBA1 revealed exacerbated synaptic loss, neuronal loss, gliosis, and microglial activation in the hippocampus of PS19::S14A mice in comparison to PS19 and WT mice. A more significant decline in cognitive function indicated by object recognition index was found in PS19::S14A mice vs. PS19 mice at 6 months. More interestingly, as compared to PS19 and WT littermates, PS19::S14A mice showed greater increases in myocardial tau proteins, ubiquitin conjugates, and cleaved caspase 3 and displayed more cardiac fibrosis, as reflected by increased mRNA expression of collagen 1 and picrosirius red staining. Echo revealed that PS19::S14A had significantly reduced fractional shortening, ejection fraction, stroke volume, and cardiac output at 9 months.

Conclusions:
The findings of this study demonstrate that genetic blockade of p-S14-RPN6 exacerbates tauopathy pathology in both the brain and heart. This is the first to have established the role of p-S14-RPN6 and, by extension, the significance of PKA-mediated proteasome activation in AD/tauopathy. Proteasome activation via augmentation of cAMP/PKA signaling should be explored for the alleviation of AD-associated brain and cardiac pathologies.
Abstract We135: Mechanistic Modeling Identifies Novel Regulators of Cardiac Hypertrophy
Authors: Watkins Lionel , Saucerman Jeffrey
Published: October 2024

Introduction:
Cardiac hypertrophy is a leading predictor of heart failure. The mechanisms that drive cardiac hypertrophy are poorly understood from a molecular and cellular perspective, due to the lack of knowledge of the governing signaling.

Hypothesis and Aims:
I hypothesize that there exist genes that regulate hypertrophy beyond the field’s current understanding that can be identified by combining the publicly available, high-throughput International Mouse Phenotyping Consortium (IMPC) database with network modeling. I aim to use a large-scale network model of cardiac hypertrophy to assess the IMPC genes’ effects on hypertrophic phenotypes and validate these findings
in vitro
to identify novel regulators.

Materials & Methods:
The IMPC was established by worldwide mouse clinics using
in vivo
models to perform single gene knockout experiments with primary phenotyping, forming a database with ~9000 genes, ~1000 of which can be associated with cardiac hypertrophy. 1
st
neighbors (genes directly interacting with the hypertrophy network model as evidenced by protein-protein interaction databases) were identified and effects on hypertrophy were assessed through the IMPC and network model knockdown simulations. When both methods suggested hypertrophic regulation, a gene was considered a candidate regulator. siRNA experiments are being performed in neonatal rat cardiomyocytes for validation. High-content imaging and qPCR are used to quantify changes in phenotype and confirm gene knockdown.

Results:
Combining the IMPC with protein-protein interaction data, 37 1
st
neighbor genes were identified. Knockdown simulation identified 2 genes (LRIG1, CBL) as negative regulators. 3 genes (VAV2, LEPR, RASA1) were identified as positive regulators. These genes became candidates for
in vitro
validation given the network-wide hypertrophic effects enacted by their knockdowns. siRNA experiments are being optimized to fully validate modeling findings.

Conclusions:
Mechanistic modeling identified 5 genes as novel regulators of cardiac hypertrophy. Sensitivity analysis highlighted known influencers of hypertrophy in the knockdown context. siRNA knockdown experiments are being performed to validate the model predictions.
Abstract We137: PGC-1α-dependent transcriptional regulatory mechanisms for tricarboxylic acid cycle genes in the heart.
Authors: Veera Samta , Sadoshima Junichi , Oka Shinichi
Published: October 2024

Many metabolic genes, including tricarboxylic acid (TCA) cycle genes, are downregulated in heart failure, which may promote the pathology due to insufficient energy production. To clarify how TCA cycle genes are downregulated in the failing heart, it is a prerequisite to clarify how these genes are transcribed in the normal heart. PGC-1α is a transcriptional co-activator that broadly induces metabolic genes through activation of transcription factors, such as ERR, Nrf1, Gabpa and YY1. Here we show that PGC-1α transcribes 13 among 14 TCA cycle genes partly through ERR, Nrf1, Gabpa and YY1. Thirteen TCA cycle genes, except for Suclg2, were downregulated in cardiac specific PGC-1α knockout (KO) mice (Relative mRNA levels in KO mice compared to wild type (WT) were CS 0.66*, Aco2 0.64*, Idh3a 0.62*, Idh3b 0.54*, Idh3g 0.54*, Ogdh 0.64*, Suclg1 0.45*, Suclg2: 1.1, Sdha 0.57*, Sdhb 0.53*, Sdhc 0.72*, Sdhd 0.57*, Fh1 0.32* and Mdh2 0.54*,p<0.05 vs. WT). ChIP-sequencing with PGC-1α antibody demonstrated that PGC-1α is localized at the promoter of thirteen TCA cycle genes, besides Suclg2. Bioinformatics analyses identified consensus binding sequences of ERR, Nrf1, Gabpa and YY1 in these promoters. Gene expression analyses with knockdown of these transcription factors demonstrated that a transcription factor whose binding sequence is found proximal to the PGC-1α localization peak transcribes the downstream genes in general. These transcription factor binding sequences were well conserved between mice and humans. ERR-, Nrf1- and Gabpa-dependent PGC-1α recruitment was verified with
in vitro
DNA binding assays using endogenous promoter sequences of Idh3a, Idh3g and Sdha. Taken together, this study clarifies a precise transcriptional mechanism for TCA cycle genes in the normal heart, which could be useful for understanding how those genes are dysregulated in the failing heart.
Abstract We143: MED12 Dysregulation Disrupts Transcriptional Programs Leading to Dilated Cardiomyopathy
Authors: Kolonay Dominic , Baskin Kedryn , Stone Kathlyene
Published: October 2024

The Mediator complex serves as a bridge to link transcriptional machinery and transcription factors (TFs) to control transcription, but detailed molecular mechanisms of transcriptional regulation by Mediator are not well-understood. Mediator is comprised of the head, middle, and tail submodules that make up the core Mediator, and the transiently associating kinase submodule. The CDK8 kinase submodule acts to regulate Mediator-RNA Polymerase II interaction. MED12 is an essential Mediator component within the kinase submodule and is required for CDK8 kinase activity. In aging models, dysregulated levels of
Med12
mRNA are detected in both atria and ventricles by qRT-PCR. MED12 protein levels are also increased in human heart failure biopsies and in the mouse heart after transverse aortic constriction (TAC)-induced heart failure[KB1] . To test the hypothesis that increased levels of MED12 contribute to development of heart failure we generated cardiac-specific
Med12
transgenic mice (cTg) by driving increased MED12 expression in cardiomyocytes using the αMHC promoter.
Med12
overexpression leads to a progressive decrease in fractional shortening by serial echocardiography. Decreased cardiac function was accompanied by increased cardiac chamber size and dilation, without cardiac fibrosis. RNA sequencing of cardiomyocytes from cTg and control mice revealed that increased levels of MED12 leads to early changes in gene expression programs. Using ingenuity pathway analysis we identified MED12-regulated gene programs including those involved in calcium cycling. MED12 is a transcriptional regulator but does not directly bind DNA. To determine how MED12 regulates gene expression we screened for TFs that interact with MED12. We performed immunoprecipitation of MED12 and by mass spectrometry and determined that MED12 interacts with the TFs MEF2, CREB, and SRF. In follow-up experiments we demonstrated that MED12 interacts with the transcription factor (TF) MEF2 to regulate calcium handling genes. Current studies are focused on determining how MED12 binding coordinates gene expression through multiple TFs in cardiomyocytes. Collectively, our data demonstrate that increased MED12 expression leads to the development of heart failure, in part by dysregulation of gene expression. Therefore, precise regulation of MED12 levels is important to maintain normal cardiac function.

[KB1]What about aging?
Abstract We147: The Utility of Cardiopulmonary Exercise Testing (CPET) Amongst Male and Female athletes to Differentiate Between Physiological Left Ventricular Enlargement and Mildly Depressed Resting Systolic Function and Athletic Individuals with Dilated Cardiomyopathy.
Authors: Marwaha Sarandeep , Fanton Zephryn , Bulleros Paulo , Simmons Rachel , Bhatia Raghav T , MacLachlan Hamish , Tome Maite , Finocchiaro Gherardo , Malhotra Aneil , Gati Sabiha , Prasad Sanjay , Papadakis Michael , Sharma Sanjay
Published: October 2024

Background:
Athletes frequently reveal a dilated left ventricle (LV),some also demonstrate a co-existent mildly depressed LV ejection fraction, raising the possibility of mild dilated cardiomyopathy (DCM). The maximal oxygen consumption(VO2max) is a valuable tool for assessing fitness, largely determined by cardiac output. References ranges derived from the general population, may have limitations when assessing athletes with primary myocardial disease. This study investigated the role of VO2max and VO2max predicted (V02pred) to differentiate between physiological LV dilatation and athletic individuals with DCM in male and female athletes.

Methods:
147 male and 35 female athletes with dilated LV(mean age 35.4years, 34.5 years respectively) underwent a 25watt cycle ergometer continuous ramp protocol. 75% males and 67% females participated in endurance sports, remaining participating in mixed sports. 52 had mild DCM, 62 defined as healthy control athletes(dilated LV) and 68 were Grey zone (dilated LV and mildly depressed LVEF)

Results:
DCM males (N=39) revealed a lower mean VO2max than male control (N=46), 34.9ml/kg/min and 48ml/kg/min respectively (p value <0.001). DCM females(N=13) showed lower VO2max of 29.9ml/min/kg than female control (N=16) who revealed similar values to male controls (48 ml/kg/min)(p value <0.001). 62 male Grey zones and 6 female Grey zone revealed lower VO2max than controls 43.1ml/min/kg and 34.1ml/min/kg respectively.

DCM females had lower VO2pred than control females 119% and 161% respectively but significantly higher than their male counterparts, means of 106% and 123% respectively (p value <0.001). Male and female grey zones had lower mean VO2pred than controls, 121% and 106% respectively. Higher VO2max of ≥38ml/kg/min and VO2pred of ≥120% gave a sensitivity, specificity of 84.7% and 77%respectively to differentiate healthy athletes and athletic DCMs in males and females. Only41.1% Grey zone athletes were able to achieve above these thresholds.

Conclusion:
Female athletes with dilated LV may reveal supranormal VO2max which can equal their male counterparts. Furthermore, athletic females with physiological or pathological LV dilatation can reveal higher VO2pred than male athletes. Most athletic DCM individuals show lower CPET parameters than controls athletes but can still achieve greater than normal measurements seen in healthy general population. VO2 may have a role in assisting in differentiating healthy athletes from athletic DCM.
Optimization of Parallel Data Transfers in Multi-Tiered Persistent Storage
Authors: Noon Nan , Getta Janusz , Xia Tianbing
Published: October 2024

A logical model of multi-tiered persistent storage provides a view of data where all available storage resources are distributed over a number of levels depending on the data transfer parameters and capacities. The efficient parallelization of data transfers in multi-tiered persistent storage is a significant challenge for a pipelined data processing model. This work examines a category of database applications implemented as sequences of operations that transfer data between the levels of multi-tiered persistent storage. The concept of EPN: Extended Petri Nets represents how database applications can be processed in parallel. A proposed transformation involves converting EPN into sequences of parallel data transfers. Additionally, a method is demonstrated for partitioning these sequences of data transfers, with the goal of reducing the total number of conflicts when data transfers occur between the levels of multi-tiered persistent storage. The paper proposes new rule-based algorithms for scheduling parallel data transfers that minimize total data transfer time. The objectives of the new algorithms are to evenly distribute the workload among the data transfer processes and reduce their idle time. Several experiments have confirmed the effectiveness of the new algorithms in generating parallel data transfer plans.
Evaluation of the Implementation of the National Community Health Policy in the Bembèrèkè-Sinendé Health District, 2023
Authors: Agonnoudé Maurice , Orou-Bodedjo Goudi , Houéhanou Corine , Houéto David
Published: October 2024

In a context shaped by the Sustainable Development Goals and the pursuit of Universal Health Coverage, the National Community Health Policy (NCHP) stands as a crucial pillar to achieve these goals by redirecting healthcare systems towards primary healthcare. The aim of this study was to assess the implementation of the NCHP in the Bembèrèkè-Sinendé health district (BSHD). This was an evaluative cross-sectional observational study with an analytical approach. A census of all active healthcare facilities in the two municipalities of the health district was conducted. A total of 28 health establishments, were included. Activity coverage rates ranged from high for home visits (46.9%) to low for other activities. Awareness raising (89.3%) and educational discussions (100%) are well conducted, while practical demonstrations and home visits encounter challenges. No significant association was found between the independent variables and the quality of the activities implemented. The results of this study provide valuable insight into the implementation of the NCHP in the BSHD. They highlight the need to strengthen the training of heads of posts. In addition, they point to the neglect of home visits in the delivery of community health care.
Beading plot: a novel graphics for ranking interventions in network evidence
Authors: Chen Chiehfeng , Chuang Yu-Chieh , Chan Edwin Shih-Yen , Chen Jin-Hua , Hou Wen-Hsuan , Kang Enoch ,   Cochrane Taiwan
Published: October 2024

Background

Network meta-analysis is developed to compare all available treatments; therefore it enriches evidence for clinical decision-making, offering insights into treatment effectiveness and safety when faced with multiple options. However, the complexity and numerous treatment comparisons in network meta-analysis can challenge healthcare providers and patients. The purpose of this study aimed to introduce a graphic design to present complex rankings of multiple interventions comprehensively.

Methods

Our team members developed a “beading plot” to summary probability of achieving the best treatment (P-best) and global metrics including surface under the cumulative ranking curve (SUCRA) and P-score. Implemented via the “rankinma” R package, this tool summarizes rankings across diverse outcomes in network meta-analyses, and the package received an official release on the Comprehensive R Archive Network (CRAN). It includes the `PlotBead()` function for generating beading plots, which represent treatment rankings among various outcomes.

Results

Beading plot has been designed based on number line plot, which effectively displays collective metrics for each treatment across various outcomes. Order on the -axis is derived from ranking metrics like P-best, SUCRA, and P-score. Continuous lines represent outcomes, and color-coded beads signify treatments.

Conclusion

The beading plot is a valuable graphic that intuitively displays treatment rankings across diverse outcomes, enhancing reader-friendliness and aiding decision-making in complex network evidence scenarios. While empowering clinicians and patients to identify optimal treatments, it should be used cautiously, alongside an assessment of the overall evidence certainty.
Post-viral symptoms and conditions are more frequent in COVID-19 than influenza, but not more persistent
Authors: Tesch Falko , Ehm Franz , Loser Friedrich , Bechmann Lars , Vivirito Annika , Wende Danny , Batram Manuel , Buschmann Tilo , Menzer Simone , Ludwig Marion , Roessler Martin , Seifert Martin , Margolis Giselle Sarganas , Reitzle Lukas , König Christina , Schulte Claudia , Hertle Dagmar , Ballesteros Pedro , Baßler Stefan , Bertele Barbara , Bitterer Thomas , Riederer Cordula , Sobik Franziska , Scheidt-Nave Christa , Schmitt Jochen
Published: October 2024

Background

Post-viral symptoms have long been known in the medical community but have received more public attention during the COVID-19 pandemic. Many post-viral symptoms were reported as particularly frequent after SARS-CoV-2 infection. However, there is still a lack of evidence regarding the specificity, frequency and persistence of these symptoms in comparison to other viral infectious diseases such as influenza.

Methods

We investigated a large population-based cohort based on German routine healthcare data. We matched 573,791 individuals with a PCR-test confirmed SARS-CoV-2 infection from the year 2020 to contemporary controls without SARS-CoV-2 infection and controls from the last influenza outbreak in 2018 and followed them up to 18 months.

Results

We found that post-viral symptoms as defined for COVID-19 by the WHO as well as tissue damage were more frequent among the COVID-19 cohort than the influenza or contemporary control cohort. The persistence of post-viral symptoms was similar between COVID-19 and influenza.

Conclusion

Post-viral symptoms following SARS-CoV-2 infection constitute a substantial disease burden as they are frequent and often persist for many months. As COVID-19 is becoming endemic, the disease must not be trivialized. Research should focus on the development of effective treatments for post-viral symptoms.
Lifetime healthcare expenditures across socioeconomic groups
Authors: Kallestrup-Lamb Malene , Marin Alexander O. K.
Published: October 2024

Background

A socioeconomic gradient affects healthcare expenditures and longevity in opposite directions as less affluent individuals have higher current healthcare expenditures but simultaneously enjoy shorter lives. Yet, it is unclear whether this cross-sectional healthcare expenditure gradient persists from a lifetime perspective. This paper analyzes lifetime healthcare expenditures across socioeconomic groups using detailed individual-level healthcare expenditure data for the entire Danish population.

Method

Using full population healthcare expenditures from Danish registries, we estimate lifetime healthcare expenditures as age-specific mean healthcare expenditures times the probability of being alive at each age. Our data enables the estimation of lifetime healthcare expenditures by sex, socioeconomic status, and by various types of healthcare expenditure.

Results

Once we account for mortality differences and all types of healthcare expenditures, all socioeconomic groups spend an almost equal amount on healthcare throughout a lifetime. Lower socioeconomic groups incur the lowest lifetime hospital expenditures, whereas higher socioeconomic groups experience the highest lifetime expenditures on long-term care services. Our findings remain robust across various socioeconomic measures and alternative estimation methodologies.

Conclusion

Improving the health status of lower socioeconomic groups to align with that of higher socioeconomic groups is costly but may ultimately reduce current healthcare expenditures. Enhanced health outcomes likely increase lifespan, leading to extended periods of healthcare consumption. However, since all socioeconomic groups tend to have similar lifetime healthcare expenditures, this prolonged consumption has limited impact on overall lifetime healthcare costs. Additionally, a significant benefit is the deferment of healthcare expenditures into the future. Overall, our results diminish concerns about socially inequitable utilization of healthcare resources while socioeconomic differences in health and longevity persist, even in a universal healthcare system.
Enhanced alveolar ridge preservation with hyaluronic acid-enriched allografts: a comparative study of granular allografts with and without hyaluronic acid addition
Authors: Kloss Frank R. , Kau Thomas , Heimes Diana , Kämmerer Peer W. , Kloss-Brandstätter Anita
Published: October 2024

Purpose

Ridge preservation is essential to restore alveolar ridge volume and to enhance esthetic and functional outcomes for dental implants. The addition of hyaluronic acid to allogeneic bone substitute materials might enhance these outcomes. This clinical study evaluated the efficacy of ridge preservation after tooth extraction using granular allografts with and without hyaluronic acid addition.

Methods

In this retrospective study, 40 patients with compromised extraction sockets were enrolled. Among them, 19 received particulate allogeneic bone substitutes (Allo), 21 received allogeneic bone substitutes with hyaluronic acid (AlloHya). Vertical and horizontal graft stability, graft shrinkage rate, and bone mineral density were assessed using radiographic measurements on CBCT scans conducted before tooth extraction, directly after ridge preservation and after four months. Patients were followed up 12 months post-implantation.

Results

Vertical height loss after 4 months was significantly greater in the Allo group (-0.82 ± 0.95 mm) compared to the AlloHya group (-0.19 ± 0.51 mm; p = 0.011). Graft shrinkage rate was 16.9 ± 11.5% (Allo) and 10.3 ± 7.7% (AlloHya) (p = 0.038). After four months, average bone density was significantly higher in the AlloHya compared to the Allo group (p = 0.004). Nearly all implants (39 out of 40) were classified as “Success” according to the ICOI scheme, with no differences in implant quality between the two study groups.

Conclusions

Improved graft stability, reduced resorption, and increased bone density were observed in hyaluronic acid-enriched allografts compared to pure allografts. Adding hyaluronic acid to allogeneic bone grafts significantly enhanced outcomes in ridge preservation.
Η συνέντευξη ως εργαλείο στην εκπαιδευτική έρευνα
Authors: Σκούμα Αργυρώ , Μαστροθανάσης Κωνσταντίνος
Published: October 2024

Σκοπός της παρούσας εργασίας είναι η ανάλυση της συνέντευξης ως ερευνητικού εργαλείου στην εκπαιδευτική έρευνα. Η συνέντευξη είναι μια πολυδιάστατη τεχνική που επιτρέπει την κατανόηση των ανθρώπινων εμπειριών, πεποιθήσεων και ιστοριών. Στο πλαίσιο της ποιοτικής έρευνας, η συνέντευξη χρησιμοποιείται για την καταγραφή βαθύτερων ανθρώπινων εμπειριών μέσω της διερεύνησης των αντιλήψεων των συμμετεχόντων. Η εργασία εξετάζει επίσης τους διάφορους τύπους συνεντεύξεων, όπως η ημιδομημένη, η μη δομημένη και η δομημένη, εστιάζοντας στις διαφορετικές προσεγγίσεις και χρήσεις τους. Επιπλέον, αναφέρει τη σημασία της επιλογής ερωτήσεων και τη διαχείριση της συνέντευξης, υπογραμμίζοντας την ανάγκη για διαφάνεια και σεβασμό προς τους συμμετέχοντες.