bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S2 from PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies
Authors: Carter Jack , Hulse Michael , Sivakumar Monisha , Burtell Jessica , Thodima Venkat , Wang Min , Agarwal Anjana , Vykuntam Komali , Spruance Jacob , Bhagwat Neha , Rager Joseph , Ruggeri Bruce , Scherle Peggy , Ito Koichi
Published: November 2023

C220 broadly suppresses DDR gene expression in cancer cells and reduces DNA repair.
Figure S1 from PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies
Authors: Carter Jack , Hulse Michael , Sivakumar Monisha , Burtell Jessica , Thodima Venkat , Wang Min , Agarwal Anjana , Vykuntam Komali , Spruance Jacob , Bhagwat Neha , Rager Joseph , Ruggeri Bruce , Scherle Peggy , Ito Koichi
Published: November 2023

Selectivity and potency of PRMT5 inhibitors analyzed by biochemical or cellular assays
FIGURE 4 from PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies
Authors: Carter Jack , Hulse Michael , Sivakumar Monisha , Burtell Jessica , Thodima Venkat , Wang Min , Agarwal Anjana , Vykuntam Komali , Spruance Jacob , Bhagwat Neha , Rager Joseph , Ruggeri Bruce , Scherle Peggy , Ito Koichi
Published: November 2023

PRMT5 inhibition induces DNA repair deficiency, and synergizes with PARP inhibition and chemotherapy in vitro and in vivo. A, Cell proliferation of HR-proficient ovarian cancer cell lines was assessed by cell-titer glo assays following 10 days treatment with C220 (n = 3). B, Immunofluorescent detection of γH2AX foci in ES-2 cells treated with C220, olaparib, or in combination for 4 days. Images are taken at 20x and are representative of two biological replicates. C, Quantitation of average γH2AX foci/nuclei (>250 nuclei/condition, n = 2). D–F, Cell proliferation assays in ovarian cancer cell lines following treatment with olaparib, cisplatin, 5-FU, or C220 alone or in combination for 10 days. Data represent percent cell proliferation relative to DMSO controls and the average response of three biological replicates is shown. G, ZIP scores were calculated from average percent cell proliferation data from drug combination using SynergyFinder. H,In vivo mouse ovarian cancer PDX (CTG-0703, BRCA1 deletion) treated with PRT543, olaparib, or in combination (n = 10 mice/group). I,In vivo mouse breast cancer PDX (CTG-1242, HR proficient) treated with PRT543, olaparib, or in combination (n = 10 mice/group). Data are represented as mean ± SEM. H and I, asterisks indicate statistical significance noted by connecting bars (*, P <0.05; **, P <0.01) using a Mann–Whitney test.
FIGURE 2 from PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies
Authors: Carter Jack , Hulse Michael , Sivakumar Monisha , Burtell Jessica , Thodima Venkat , Wang Min , Agarwal Anjana , Vykuntam Komali , Spruance Jacob , Bhagwat Neha , Rager Joseph , Ruggeri Bruce , Scherle Peggy , Ito Koichi
Published: November 2023

C220 broadly suppresses DDR Gene expression in ovarian and breast cancer cells. A, Volcano plots from RNA-seq data in breast (MCF7) and ovarian (A2780) cancer cell lines treated with 100 nmol/L C220 for 4 days (n = 3). Select DDR genes are highlighted. B, Top eight downregulated hits from KEGG pathway analysis of significantly DEGs from MCF7 and A2780 RNA-seq data (q value < 0.01, n = 3). C, Clustered heat map of HRD signature genes in C220-treated MCF7 cells (n = 3). D, Dose-dependent downregulation of select DDR genes was validated by qRT-PCR (fold change ddCT from DMSO control) following treatment with C220 for 4 days (n = 3). Data are represented as mean ± SEM. E and F, Western blots highlighting dose-dependent downregulation of select DDR proteins following treatment with C220 for 4 days (n = 2).
FIGURE 1 from PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies
Authors: Carter Jack , Hulse Michael , Sivakumar Monisha , Burtell Jessica , Thodima Venkat , Wang Min , Agarwal Anjana , Vykuntam Komali , Spruance Jacob , Bhagwat Neha , Rager Joseph , Ruggeri Bruce , Scherle Peggy , Ito Koichi
Published: November 2023

PRMT5 gene expression positively correlates to DDR gene expression in cancer cells. A, Heat map of Pearson correlation coefficients between PRMT5 and HRD signature genes for breast, ovarian, pancreatic, and prostate cancer cell lines from CCLE (heat map is sum ranked). B, Dot plots showing PRMT5 expression relative to key DDR genes in ovarian and breast cancer cell lines (dots represent cell lines). C, Pearson correlation coefficient r values were deconvoluted and shown in bar graph. D, mRNA expression of select correlated DDR genes by qPCR following transient genetic knockdown of PRMT5 by shRNA in MCF7 cells (n = 2).
Data from PRMT5 Inhibitors Regulate DNA Damage Repair Pathways in Cancer Cells and Improve Response to PARP Inhibition and Chemotherapies
Authors: Carter Jack , Hulse Michael , Sivakumar Monisha , Burtell Jessica , Thodima Venkat , Wang Min , Agarwal Anjana , Vykuntam Komali , Spruance Jacob , Bhagwat Neha , Rager Joseph , Ruggeri Bruce , Scherle Peggy , Ito Koichi
Published: November 2023

Abstract
Expression of protein arginine methyltransferase 5 (PRMT5) is highly positively correlated to DNA damage repair (DDR) and DNA replication pathway genes in many types of cancer cells, including ovarian and breast cancer. In the current study, we investigated whether pharmacologic inhibition of PRMT5 downregulates DDR/DNA replication pathway genes and sensitizes cancer cells to chemotherapy and PARP inhibition. Potent and selective PRMT5 inhibitors significantly downregulate expression of multiple DDR and DNA replication genes in cancer cells. Mechanistically, PRMT5 inhibition reduces the presence of PRMT5 and H4R3me2s on promoter regions of DDR genes such as BRCA1/2, RAD51, and ATM. PRMT5 inhibition also promotes global alternative splicing changes. Our data suggest that PRMT5 inhibition regulates expression of FANCA, PNKP, and ATM by promoting exon skipping and intron retention. Combining C220 or PRT543 with olaparib or chemotherapeutic agents such as cisplatin demonstrates a potent synergistic interaction in breast and ovarian cancer cells in vitro. Moreover, combination of PRT543 with olaparib effectively inhibits the growth of patient-derived breast and ovarian cancer xenografts. Furthermore, PRT543 treatment significantly inhibits growth of olaparib-resistant tumors in vivo. These studies reveal a novel mechanism of PRMT5 inhibition and suggest beneficial combinatorial effects with other therapies, particularly in patients with tumors that are resistant to therapies dependent on DNA damage as their mechanism of action.
Significance:
Patients with advanced cancers frequently develop resistance to chemotherapy or PARP inhibitors mainly due to circumvention and/or restoration of the inactivated DDR pathway genes. We demonstrate that inhibition of PRMT5 significantly downregulates a broad range of the DDR and DNA replication pathway genes. PRMT5 inhibitors combined with chemotherapy or PARP inhibitors demonstrate synergistic suppression of cancer cell proliferation and growth in breast and ovarian tumor models, including PARP inhibitor–resistant tumors.
Abstract 12506: Implantable Cardioverter Defibrillators for Primary Prevention in Patients With Ischemic and Non Ischemic Cardiomyopathy: A Meta-Analysis of 15 Randomized Controlled Trial
Authors: Jaiswal Vikash , Jaiswal Akash , Mohamed Taha Amira , Kalra Kriti , Nasir Yusra
Published: November 2023

Background:
The evidence to support implantable cardioverter defibrillator (ICD) in patients with ischemic and nonischemic cardiomyopathy for prevention of sudden cardiac death (SCD) is not robust, with conflicting results in randomized controlled trials.

Objective:
We aim to evaluate the impact of ICD therapy with conventional care for the primary prevention of death of various causes in adults with ischemic and nonischemic cardiomyopathy.

Methods:
We performed a systematic literature search on the electronic database for relevant articles from inception until 15th May 2022.

Results:
A total of 15 randomized controlled trials involving 9,999 patients: 9 (6523 patients) addressed ischemic cardiomyopathy, and 6 studies (3476 patients) reported nonischemic cardiomyopathy. The mean follow-up duration was 3.02 years. Pooled analysis showed that ICD therapy significantly reduced the risk of ACM (HR, 0.75(95%CI: 0.64-0.88), P<0.001) from the control group. The magnitude of reduction was similar with ischemic (HR, 0.75(95%CI: 0.58-0.96), P=0.02), nonischemic (HR, 0.76(95%CI: 0.64-0.90), P<0.01). There was 67% reduction in SCD among ICD therapy group (OR, 0.33(95%CI: 0.25-0.44), P<0.00001) compared to the control, a similar trend was observed in both ischemic (OR, 0.39(95%CI: 0.28-0.56), P<0.00001), and nonischemic cardiomyopathy (OR, 0.24(95%CI: 0.15-0.38), P<0.00001). The ICD therapy group had a significant reduction of 65% reduction in arrhythmia-related death compared to control in ischemic cardiomyopathy (OR, 0.35(95%CI: 0.19-0.64), P<0.001). However, there was a trend of 23% in cardiovascular mortality in the ICD group (OR, 0.77(95%CI: 0.58-1.02), P=0.07) but unable to reach statistical significance.

Conclusion:
Overall, primary prevention with ICD therapy reduced the incidence of all-cause mortality and sudden cardiac death among ischemic and nonischemic cardiomyopathy patients.
Abstract 12510: Spatial and Temporal Effects on Human Health Following a Serious Natural Disaster
Authors: Suzuki Yurika , senda atsushi
Published: November 2023

Introduction:
The effects of disasters can be classified into direct effects and indirect effects. Although direct effects of disasters have been extensively reported, the reports on indirect effects are scarce. We analysed the long-term spatiotemporal effects of The Great East Japan Earthquake, which occurred on March 11, 2011, to elucidate its direct and indirect effects.

Methods:
The spatial analyses and the temporal analyses were performed using the data from Japanese Diagnosis Procedure Combination (DPC) database from August 01, 2010 to March 31, 2015.

Results:
The number of patients in DPC-participating hospitals showed apparent decrease with odds ratio of 0.46 (25th-75th percentile 0.10-0.80) immediately after the earthquake (Figure1), and the crude death ratio increased significantly with odds ratio of 1.78 (25th-75th percentile 1.13-2.26), lasting for 12 months (Figure2). This change was not only seen in the disaster area but in the broader area of Japan. The proportion of patients admitted to hospitals due to malignant disease largely decreased (53.8% before earthquake, 34.8% within 1 year after earthquake, odds ratio 0.65), and the proportion of patients admitted to hospitals due to cardiovascular disease largely increased (13.1% before earthquake, 28.5% after earthquake, odds ratio 2.17) within 1 year after the earthquake.

Conclusions:
A wide-scale natural disaster affects the number of patients and mortality prominently in the disaster area for at least 1 year, especially in patients with cardiovascular disease. The results of this study provide important information for development of future disaster control measures.
Abstract 12513: Anti-Inflammatory Effect of Statin Among Patients With Rheumatoid Arthritis: A Network Meta-Analysis of Randomized Controlled Trials
Authors: Jaiswal Vikash , Jaiswal Akash , Hanif Muhammad , Jha Mayank , Attia Abdelrahman M , Gupta Shiva , Ramadan Alaa , Saleeb Marina , Ang Song Peng , Kalra Kriti
Published: November 2023

Background:
Rheumatoid arthritis (RA) have shown to be associated with a higher risk of acute coronary syndrome and atrial fibrillation. However, the impact of statin among RA patients is not well studied, with conflicting results.

Objective:
We aim to compare the anti-inflammatory effect of different statin drugs among patients with rheumatoid arthritis in this network meta-analysis (NMA).

Methods:
We performed a systematic literature search on the electronic database for relevant randomized controlled trials (RCTs) from inception until 25th May 2023. A network meta-analysis was conducted to evaluate the anti-inflammatory effect of different statin drugs among RA patients. We presented results as mean difference (MD) and 95% confidence interval.

Results:
A total of 16 RCTs with a total of 3,886 patients (1,938 in the statin group and 1,948 in the non-statin group) were included. The network meta-analysis showed that Atorvastatin was the only intervention that significantly decreased the mean difference of all the inflammatory predictors including ESR (MD= -6.77, 95% CI= [-9.52, -4.01], P<0.01), CRP (MD= -2.93, 95% CI= [-5.06, -0.79], P<0.01), DAS28 (MD= -0.62, 95% CI: [-0.85,-0.39], P<0.01); and IL-6 (MD= -9.28, 95% CI= [-16.04,-2.53], P<0.01) in RA patients when compared to placebo. However, Atorvastatin showed no statistically significant difference for TNF compared to Placebo (MD: -31,51 with 95% CI [-75.54,12.52], P = 0.16). Regarding the other interventions, they showed no significant effect on the mean difference of any of the inflammatory markers.

Conclusion:
The findings of our study indicate that atorvastatin is associated with a significant decrease in the inflammatory markers among rheumatoid arthritis patients compared with other statin therapy. Overall, these results have significant implications for patients with RA who would benefit from the stain anti-inflammatory effect.
Abstract 12517: The Racial Disparity Among the Clinical Outcomes, and Management Utilization in Atrial Fibrillation Patients: A Meta Analysis
Authors: Jaiswal Vikash , Jaiswal Akash , Deb Novonil , Attia Abdelrahman , Ang Song Peng , Evbayekha Endurance O , Gupta Shiva , Prem Anand Dharshana , Patel Nirmit
Published: November 2023

Background:
Although a higher burden of atrial fibrillation (AF) risk factors exists among the Black population, their prevalence of AF is less than White patients due to the under-diagnosis of minority groups and disparities in their management and outcomes.

Objective:
We aim to evaluate the disparities among the clinical outcomes post-AF, utilization of oral anticoagulants, and catheter ablation among Black and White race of patients.

Methods:
We systematically searched all electronic databases from inception until 27th May 2023. The primary outcome was all-cause mortality (ACM). Secondary outcomes include incidence of stroke, utilization of direct oral anticoagulants (DOAC), and catheter ablation.

Results:
A total of 11 studies with 1915540 patients were included in the final analysis (1771768 patients in the White group and 143772 patients of Black race). Pooled analysis of clinical outcomes shows that Black patients were having a higher risk of all-cause mortality (HR, 1.39(95%CI:1.09-1.75), P<0.01). Similarly compared with White patients, the odds of initiating DOAC therapy (OR, 0.85(95%CI: 0.80-0.91), P<0.001), and utilization of catheter ablation (OR, 0.69(95%CI: 0.52-0.86), P<0.001) were significantly lower in Black patients.

Conclusion:
Black patients with atrial fibrillation are found to be associated with higher mortality and lower utilization of management approaches like use of DOAC, and catheter ablation.
Abstract 12528: DNA Methylation Profiles of 3 Major CHIP Subtypes Provide Insight Into Underlying Epigenetic Mechanisms
Authors: Kirmani Sara , Huan Tianxiao , Joehanes Roby , Liu Chunyu , Ma Jiantao , Bick Alexander G , Heard-Costa Nancy , Murabito Joanne , Levy Daniel
Published: November 2023

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon characterized by the presence of clonal populations of hematopoietic-derived cells in whole blood that harbor functional leukemogenic somatic mutations. Despite the well-established associations between aging and CHIP and aging and genome-wide DNA methylation (DNAm), the association between CHIP and changes in DNAm remains to be fully elucidated. To fill this knowledge gap, an epigenome-wide association study of CHIP was performed in Framingham Heart Study participants from the Offspring cohort (n
total
= 1594; 54% women; mean age 67 years) using whole blood derived DNA to elucidate the DNAm profiles of any CHIP and the three most frequently mutated CHIP driver genes
DNMT3A, TET2
, and
ASXL1/2
. Linear mixed models were used to test associations between CHIP status as the predictor variable and genome-wide DNAm of CpG sites as the outcome, with adjustment for age, age
2
, sex, smoking, 33 surrogate variables, and familial relatedness. From the analysis, 189 CpGs were found to be associated with any CHIP, and 139, 107, and 4 were associated with
DNMT3A
,
TET2
, and
ASXL1/2
CHIP, respectively (Bonferroni corrected P<1х10
-7
). The CpGs associated with the
DNMT3A
,
TET2
, and
ASXL1/2
CHIP were distinct. Genome-wide DNAm directions of effect were similar for
DNMT3A
and
ASXL1/2
CHIP but opposite to
TET2
. Gene expression analysis identified CpG-gene transcript pairs for any CHIP and CHIP subtypes. The most significant gene sets were enriched in pathways related to immune response and hematopoietic cell lineage. Two-sample Mendelian randomization analysis was additionally conducted to investigate whether methylation at CHIP-associated CpGs causally influences risk of cardiometabolic traits and all-cause mortality. Evidence of a putative causal role of CHIP-associated CpGs in relation to several traits, including BMI and hypertension, and all-cause mortality was found. Taken together, we identified CpGs associated with CHIP and with the three major CHIP driver genes, elucidated their methylomic signatures, identified CpG-transcript pairs, and provided support for a potential causal role of CHIP-associated CpGs in relation to cardiometabolic traits and all-cause mortality.
Abstract 12547: Incidence of Pulmonary Hypertension in the Echocardiographic Referral Population
Authors: Garry Jonah D , Kundu Suman , Annis Jeffrey , Alcorn Charles , Eden Svetlana , Smith Emily K , Maron Bradley A , Freiberg Matthew S , Brittain Evan
Published: November 2023

Background:
Incident rates (IRs) for pulmonary hypertension (PH) using diagnostic data rather than diagnostic codes (DC) have not been reported. We examined PH IRs, risk factors, and mortality among patients (pts) referred for echocardiography (TTE) in a national healthcare system and a separate tertiary care center.

Methods:
Pulmonary artery systolic pressure (PASP) estimates were extracted from the Veterans Affairs (1999-2020) and Vanderbilt (1994-2020) systems. PH was defined as PASP >35 mmHg. Individuals free of PH at baseline were followed through incident PH, death, or censored at end of study. Secondary outcome was mortality rate (MR) after incident PH. We used Poisson regression to estimate IRs and cox models for hazard ratios.

Results:
We identified 245,067 veterans (60 years [IQR 55-64], 94% male, 20% Black) and 117,526 VUMC pts (60 years [IQR 46-70], 46% male, 11% Black) free of PH at baseline. Only 22% of pts with TTE-based PH had a DC for PH. PH IRs and adjusted hazard were substantially higher in pts with HF or COPD and highest in pts with both (
Table 1
). MR after incident PH was highest in pts with both HF and COPD and lowest in pts without either
(Figure 1A
). MRs increased markedly at PASP values >45mmHg (
Figure 1B
). Independent risk factors for incident PH included older age (HR 1.07; 95%CI 1.06-1.09), male sex (HR 1.24; 95%CI 1.17-1.30), black race (HR 1.10; 95%CI 1.07-1.13), and cardiometabolic comorbidities.

Conclusions:
PH IRs estimated by raw diagnostic data are higher than DC-based IRs and strongly associated with HF and COPD. PASP >45mmHg at the time of incident PH is associated with high mortality.
Abstract 12552: Unmasking Unstable Angina: The Crucial Influence of Chest Pain Perception in Hospital Management Strategies
Authors: Prata Mateus A , Ohe Louis N , Vilalva Kelvin H , Lemos Lucas , Mota Diandro M , SMANIO PAOLA E
Published: November 2023

Introduction:
Managing unstable angina (UA) poses a significant challenge due to its subjective diagnosis and underrepresentation in pivotal clinical trials that have greatly influenced current practices. The aim of this study is to determine the key variables that impact the management of UA in a referral cardiology hospital.

Hypothesis:
In addition to prognostic scores, other factors such as the nature of chest pain may have a relevant role in the management of UA.

Methods:
This retrospective cohort study enrolled patients consecutive hospitalized with a diagnosis of UA from July 16, 2018 to February 28, 2020. The primary objective was to analyze the factors associated with the utilization of either an invasive or non-invasive strategy. The secondary objective sought to identify the factors associated with the presence of obstructive coronary artery disease (CAD) or ischemia, as determined by the results of complementary tests. Between-group comparisons were performed using multiple logistic regression analysis, with statistical significance set at a 5% level.

Results:
A total of 729 patients were included in the study, with a mean age of 62.9 years, with a male predominance (64.6%). Factors significantly associated with an invasive strategy were smoking (p = 0.001), type of chest pain (p < 0.001), angina "in crescendo" (p = 0.006), TIMI risk (p = 0.006), and HEART score (p = 0.011). In the multivariate analysis, current smokers (OR 2.23, CI 95% 1.13-4.8) and type A chest pain (OR 3.39, CI 95% 1.93-6.66) were independently associated with the invasive strategy. Regarding the presence of obstructive CAD or ischemia, male gender (p = 0.032), exertional chest pain (p = 0.037), Diamond-Forrester (p = 0.026) and TIMI risk (p = 0.001) showed significant associations. In the multivariate analysis, the type of chest pain (type B chest pain: OR 0.6, CI 95% 0.38-0.93, p = 0.026) and presence of previous CAD (OR 1.42, CI 95% 1.01-2.0, p = 0.048) were independently associated with obstructive CAD or ischemia.

Conclusion:
Chest pain type is not only instrumental in diagnosing UA but also critical in shaping the suitable treatment approach. Our study emphasizes the significance of integrating pain traits with guidelines-endorsed scoring systems for optimal management.
Abstract 12561: Intravascular Lithotripsy Use for Percutaneous Fontan Pathway Rehabilitation in an Adult With Fontan Pathway Obstruction
Authors: Galeano Lovera Santiago F , Pollak Peter , Phillips Sabrina D , Gonzalez Carolyn , Cabalka Allison K , Bravo Jaimes Katia M
Published: November 2023

Introduction:
Fontan pathway obstruction is a serious complication characterized by an anatomical or functional narrowing anywhere in the cavo-pulmonary pathways. Here we report the first case where an innovative Fontan conduit rehabilitation procedure with intravascular lithotripsy was used achieving a significant increase in the pathway size.

Case:
A 28-year-old male with tricuspid atresia status-post Fontan palliation (age 23 months) with bare metal stent implant to treat obstruction at age 15, presented with syncope, ascites and varicose veins. Imaging studies revealed a cirrhotic liver morphology and Fontan pathway obstruction with minimal diameter of 12 mm. Cardiac catheterization confirmed severe Fontan conduit obstruction in addition to LPA stenosis. Serial covered Cheatham-Platinum stents were implanted for conduit coverage followed by Palmaz stents. Non-compliant Atlas balloon dilation to 20 atm was performed without expansion of the Fontan pathway beyond 12 mm due to severe calcification. A 7.0 x 60 mm shock-wave lithotripsy balloon was added alongside the Atlas balloon to modulate the heavily calcified wall with subsequent expansion of the conduit to 21 mm after inflating the Atlas balloon to 14 atm.

Discussion:
Several studies demonstrated that transcatheter stenting of stenotic Fontan conduits can be safely performed. Intravascular lithotripsy has emerged as a novel therapy for the treatment of coronary vascular calcification. We report the first case of an innovative percutaneous Fontan conduit rehabilitation procedure using a lithotripsy shock wave balloon in an adult with severely calcified Fontan pathway obstruction and prior stents, achieving a 75% increase in the pathway size without significant complications. Further studies are needed to evaluate the long-term safety and efficacy of this novel approach, but this case presents an exciting option for future directions in the percutaneous treatment of Fontan pathway obstruction.
Abstract 12563: Is Cardiometabolic Risk Reduction Sustainable in Routine Practice?
Authors: Hernandez Sevillano Jose Joel , Babagoli Masih , Mellacheruvu Pranav , Chen Yitong , Liu Shelley , Johnson Janet , Fuster Valentin , mechanick Jeffrey
Published: November 2023

Introduction:
Sustained cardiometabolic risk reduction is elusive in routine practice.

Hypothesis:
A multidisciplinary (endocrinology, cardiology, nutrition, diabetes technology/education, and exercise physiology) preventive cardiology center focused on the cardiometabolic-based chronic disease (CMBCD) model can exert long-term risk reduction in patients with and without cardiometabolic presentations.

Methods:
Yearly attainment of guideline-directed medical therapy targets of the metabolic driver at the most advanced stage in patients from the Center for Clinical Cardiovascular Health at Mount Sinai Heart with adiposity-, dysglycemia-, hypertension-, and lipid-based chronic disease with predisease, disease, or complications was measured. The main outcome was sustainability rate.

Results:
A total of 270 patients with a mean follow-up of 4.0±1.2 years were included. Sustainability, defined as target attainment in the year in question and in any other previous year(s), was observed in 93/127 (73%), 81/116 (70%), 55/80 (69%), 40/54 (74%), and 11/13 (85%) patients in years of engagement 2, 3, 4, 5, and 6, respectively. The median (interquartile range) number of years reaching the target for sustainers observed was: 2 (2-2); 3 (2-3); 3 (2-3.5); 4 (2-5); 5 (4-6) for patients with 2, 3, 4, 5, or 6 years of engagement at the Center.

Conclusions:
High sustainability rates for cardiometabolic risk reduction were observed in a multidisciplinary preventive cardiology center based on the CMBCD model with a focus on lifestyle medicine, in patients with and without cardiometabolic presentations.
Abstract 12567: A Novel Mouse Model Replicates Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia
Authors: Schimmel Katharina , Ichimura Kenzo , Andruska Adam , Spiekerkoetter Edda F
Published: November 2023

Background:
1 in 5,000 people worldwide present with Hereditary Hemorrhagic Telangiectasia (HHT), a vascular disorder that is most frequently caused by mono-allelic loss of function either of the gene
ALK1,
or
ENG
. Up to 50% of patients with HHT develop Pulmonary Arteriovenous Malformations (pAVMs), abnormal connections between arteries and veins. Health consequences include stroke, or rupture of the pAVM with life threatening bleedings. How pAVMs develop is unknown and there is no cure.

Aims:
We here aim at generating the first mouse model with pAVMs in HHT to address how pAVMs arise and grow, and to enable preclinical drug testing. Our goal is to produce the characteristic sac-like appearance of pAVMs in random locations of the lung by replicating probable underlying genetic events of HHT patients.

Methods and Results:
pAVMs occur in a focal fashion, despite a systemic mono-allelic loss of function in either one of the genes
ALK1
or
ENG
in HHT. Recently, somatic mutations causing a local bi-allelic loss of
ALK1
or
ENG
were identified in skin vascular abnormalities of HHT patients, most likely in clonally expanding endothelial cells (ECs). To recapitulate this locally confined complete loss of function of
Alk1
in the mouse lung, we generated a tamoxifen-inducible (TM) Cre-lox mouse in which bi-allelic deletion of
Alk1
can be induced only in a subset of ECs of mouse pulmonary capillaries. TM was administered in P11 or P13 old mice. 5-6 days post-injection, focal sac-like structures of the pulmonary arteries with potential connections to veins were visible in random locations of the mouse lungs of
Alk1
mutants, but not control lungs.

Conclusion:
Bi-allelic deletion of
Alk1
in ECs of mouse pulmonary general capillaries closely mimics a local loss of function somatic mutation in the single functional allele of
ALK1
, as uncovered in vascular abnormalities of patients with HHT. Our novel mouse model is the first to faithfully recapitulate the focal and sporadic occurrence of pAVM-like structures seen in HHT patients. This will now enable us to identify molecular drivers of pAVM formation and test therapeutics to prevent or halt pAVM development.
Abstract 12569: The Roles of microRNA in Preeclampsia Induced Fetal Sex-Specific Endothelial Dysfunction
Authors: Yang Allison , Senica Savannah , Pontifex Tasha , Zhou Chi
Published: November 2023

Introduction:
Preeclampsia (PE) is a hypertensive disorder that complicates 5-10% of human pregnancies and leads to high fetal morbidity and mortality. Maternal obesity increases the risks of PE by 3-fold in association with elevated circulating pro-inflammatory cytokines which are related to endothelial dysfunction observed in PE. MiR146a-5p is a cardiovascular disease-associated miRNA that regulates endothelial cell responses. We have previously reported fetal sex-specific fetal endothelial dysfunction in PE. Although miR146a-5p has been reported to be dysregulated in PE HUVECs, the role of miR146a-5p in PE-dysregulated fetal sex-specific endothelial dysfunction is unclear.

Hypothesis:
MiR146a-5p differently mediate PE-induced sex-specific fetal endothelial dysfunction in lean and obese pregnancies.

Methods:
Human umbilical vein endothelial cells (unpassaged, P0-HUVECs; 5-7 days of culture, P1-HUVECs) were isolated immediately after delivery from normotensive (NT; 39±0.5 wks) and PE (38±0.5 wks) pregnancies (lean and OB) with female (F) and male (M) fetuses. Expression of miR146a-5p was examined in P0-HUVECs using RT-qPCR (n=8-10/group). Bioinformatics analysis was performed with our existing RNAseq data to identify PE-dysregulated miR146a-5p target genes in HUVECs. Endothelial monolayer integrity (MI) responses to cytokines were examined in P1 HUVECs with and without miR146a-5p overexpression and knockdown (n=5-7/group/assay).

Results:
PE upregulated miR146a-5p in lean F-HUVECs, while downregulated miR146a-5p in obese M-HUVECs. PE differentially dysregulated vascular/endothelial function-associated miR146a-5p target genes (e.g., TNFα-/TGFβ-signaling pathways) in F&M HUVECs. PE further reduced the TNFα-weakened MI in F and M HUVECs in both lean and OB pregnancies. TGFβ1 strengthened MI only in F-HUVECs, which was abolished in lean PE-F-HUVECs and was further decreased in OB PE-F-HUVEC. Knockdown of miR146a-5p rescues the PE-impaired MI responses to TNF-α and TGF-β1 in lean F-HUVECs but only rescues PE-impaired MI responses to TGF-β1 in OB F-HUVECs.

Conclusions:
MiR146a-5p plays important roles in mediating PE-induced fetal sex-specific fetal endothelial dysfunction in lean and obese pregnancies.
Abstract 12593: Associations of Serum Uric Acid and Cardiovascular Events in a Clinical Trial of IL-1β Blockade
Authors: Adamstein Nicholas H , MacFadyen Jean , Weber Brittany N , Libby Peter , Solomon Daniel , Ridker Paul M
Published: November 2023

Background:
Serum uric acid (SUA) associates with CV events, mortality, and gout. We assessed whether SUA predicts CV risk in a trial of IL-1β inhibition with canakinumab, a therapy known to reduce both CV events and gout.

Aims:
To validate associations between SUA and CV risk in a large cohort with chronic CAD and determine whether these associations were altered by IL-1β blockade or baseline renal function.

Methods:
The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) randomized 10,061 patients with prior MI and hsCRP ≥ 2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo subcutaneously every four weeks. SUA levels were obtained at baseline. Cox proportional hazards models compared the outcomes of major adverse cardiovascular events (MACE), CV death (CVD), and all-cause mortality (ACM) among those with baseline SUA ≤ 6.8 mg/dL, 6.8- 9.0 mg/dL, and ≥ 9.0 mg/dL (format: HR (95% CI); p). This analysis was repeated separately within canakinumab, placebo, eGFR ≥ 60 mL/min, and eGFR < 60 mL/min sub-groups.

Results:
High SUA associated with MACE (1.66 (1.38-1.99); p<0.0001), CVD (2.52 (1.98-3.21); p<0.0001), and ACM (2.43 (2.01-2.94); p<0.0001) compared to low SUA. These associations were minimally attenuated after adjustment for age, sex, BMI, smoking, hypertension, diabetes, LDL-C, and hsCRP. After further adjusting for eGFR and diuretic use, high SUA independently predicted CVD and ACM. In the IL-1β blockade arm, high SUA associated with MACE (1.82 (1.46-2.26); p<0.0001), CVD (2.80 (2.10-3.73); p<0.0001), and ACM (2.72 (2.17-3.40); p<0.0001). In participants with normal eGFR, high SUA associated with CVD and ACM, but not MACE.

Conclusions:
These data from a large cohort of patients with chronic CAD confirm that individuals with elevated SUA have increased CV risk despite aggressive medical therapies. IL-1β blockade did not modify these associations. Future trials may consider inclusion of patients with high SUA and CKD as a method to increase absolute risk.
Abstract 13815: Therapeutic Effects of Empagliflozin in Diabetic Patients After Acute Myocardial Infarction: Systematic Review and Meta-Analysis With Trial Sequential Analysis
Authors: Mouffokes Adel , Soliman Youssef , Amer Basma E , Umar Tungki Pratama , Abdelazeem Basel
Published: November 2023

Introduction:
Empagliflozin is a new sodium-glucose transporter protein 2 (SGLT2) inhibitor. In addition to its anti-hyperglycemic effect, recent studies suggested that it may improve cardiac outcomes in diabetic patients with acute myocardial infarction. This systematic review and meta-analysis aims to test this hypothesis.

Methods:
We comprehensively searched PubMed, Scopus, Cochrane, and Web of Science. We included studies comparing empagliflozin versus placebo in diabetic patients with acute myocardial infarction. Our outcomes were the changes in plasma N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), left ventricular ejection fraction% (LVEF%), and hemoglobin A1c (HbA1c) levels. We performed Trial Sequential Analysis (TSA), and we used mean difference (MD) and 95% confidence interval (CI) as our effect size with a random effects model.

Results:
Five studies (one cohort study and four randomized controlled trials), compromising 751 patients, were included. Empagliflozin significantly increased LVEF compared to placebo (MD = 1.80, 95% CI [0.50, 3.10],
P
=0.007), however, the TSA curve did not cross the conventional boundary for statistical significance, indicating that the available evidence did not reach the predetermined threshold. On the other hand, we observed no significant difference between the two groups in terms of NT-pro-BNP and HbA1c (MD = -136.59, 95% CI [-293.43, 20.25],
P
=0.09; MD= -0.72, 95% CI [-1.73, 0.29],
P
=0.16, respectively).

Conclusions:
Our meta-analysis reveals that among diabetic patients with acute myocardial infarction, empagliflozin failed to improve cardiac parameters such as LVEF and NT-pro-BNP without providing additional benefits in reducing HbA1c levels. Therefore further large-scale RCTs are warranted to ascertain our findings.
Abstract 13817: Very Short-Term Blood Pressure Variability by Pulse Transit Time-Based Measurements During Sleep Predicts Future Cardiovascular Events in Patients With Ischemic Heart Disease
Authors: Ogawara Ryo , Misaka Tomofumi , Ichimura Shohei , Tomita Yusuke , Tani Tetsuya , Sato Yu , Miura Shunsuke , Yokokawa Tetsuro , Sato Akihiko , Shimizu Takeshi , Sato Takamasa , Oikawa Masayoshi , Kobayashi Atsushi , Yoshihisa Akiomi , Takeishi Yasuchika
Published: November 2023

Background:
Blood pressure (BP) variability (BPV) is recognized as an independent factor associated with cardiovascular (CV) events. However, monitoring very short-term BPV, which occurs within seconds or minutes remains challenging, and its prognostic impact has yet to be established. In a previous study, we reported that pulse transit time (PTT) enabled monitoring beat-to-beat BP, which is useful for evaluating very short-term BPV during sleep.

Aims:
This study aimed to clarify the prognostic relevance of PTT-based very short-term BPV during sleep.

Methods and Results:
We conducted a prospective study involving 206 consecutive hospitalized patients (mean 67.6 years old, 78.1% male) with ischemic heart disease. PTT-driven BP was continuously recorded during the night. To assess very short-term BPV, we defined the PTT index as the average number of acute transient rises in systolic BP (≥12 mmHg) within 30 s/h, and the standard deviation (SD) of PTT-BP was calculated. We followed up with patients for a median of 759 days and observed 49 CV events, including cardiac death, worsening heart failure, acute coronary syndrome, and ischemic stroke. Kaplan-Meier analysis revealed that patients with higher PTT index, as well as higher SD of mean and diastolic PTT-BP were associated with increased CV events (
Figure
). In a multivariate Cox proportional hazards analysis, after adjusting for confounding variables, PTT index, as well as SD of mean and diastolic PTT-BP were independently associated with increased risks of adverse events (hazard ratio, 1.019, 1.245, and 1.244; P = 0.02, 0.04, and 0.09, respectively).

Conclusions:
PTT-index and SD of mean and diastolic BP during the night, which represent measures of very short-term BPV, predicted the future risk of CV events in patients with ischemic heart disease through the PTT-driven approach and may serve as a target to reduce the residual risk in such patients.
Abstract 13824: Salsalate Does Not Improve Endothelial Function and Insulin-Stimulated Vasodilation in Patients With Metabolic Syndrome
Authors: Sullivan Alexander E , Shardelow Emily M , Aday Aaron W , Wells Quinn S , Freiberg Matthew S , Beckman Joshua A
Published: November 2023

Background:
Insulin resistance accelerates systemic inflammation and vascular dysfunction. Salsalate suppresses inflammation and may improve insulin sensitivity and insulin-mediated, endothelium-dependent vasodilation.

Hypothesis:
We hypothesized that salsalate treatment would improve insulin-stimulated forearm blood flow (FBF) in volunteers with metabolic syndrome compared to placebo.

Methods:
We conducted a randomized, double-blind, placebo-controlled crossover trial (NCT00760019) evaluating 4-weeks of salsalate 1.5 grams TID on insulin-stimulated FBF during an insulin clamp in patients with and without metabolic syndrome.

Results:
Nineteen patients received salsalate (13 metabolic syndrome and 6 healthy controls). Patients with metabolic syndrome were older (36.3 vs 57.1 years old, p=0.002) with higher BMIs (33.9 vs 25.5 kg/m
2
, p=0.001) and higher insulin levels (10.8 vs 4.3 μU/mL, p=0.01). Those with metabolic syndrome had impaired insulin sensitivity by Homeostatic Model Assessment for Insulin Resistance (HOMA IR, 2.66 vs 0.87, p=0.005) and Matsuda Index (MI, 5.81 vs 3.32, p=0.001). After salsalate treatment, insulin sensitivity was unchanged (Panel A & B) and there was no significant reduction in insulin levels (Panel C) or inflammation by C-reactive protein (Panel D). Insulin stimulation increased FBF in patients treated with placebo (p=0.012) and salsalate (p=0.003), but salsalate blunted the FBF response in those with metabolic syndrome (p=0.022, Panel E). In multivariable linear regression, metabolic syndrome, HOMA IR, and MI associated with insulin-stimulated FBF independent of salsalate treatment.

Conclusion:
Salsalate improved neither insulin sensitivity nor systemic inflammation, and it blunted insulin-stimulated vasodilation in patients with metabolic syndrome. Salsalate does not modulate systemic inflammation and worsens arteriolar endothelial dysfunction in patients with metabolic syndrome.
Abstract 13828: Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARADIGM-HF Proteomic Sub-Study
Authors: Patel-Murray Natasha , Zhang Luqing , Claggett Brian , Xu Dongchu , Serrano-Fernandez Pablo , Wandel Simon , Xu Huilei , Healey Margaret , Turner Gordon , Chen Chien-Wei , Zhao Faye , CHUTKOW WILLIAM A , Yates Denise , ODonnell Christopher , Prescott Margaret , Lefkowitz Martin P , Gimpelewicz Claudio R , Beste Michael , Gou Liangke , Desai Akshay S , Jhund Pardeep S , Packer Milton , Pfeffer Marc A , Redfield Margaret M , Rouleau Jean L , ZANNAD Faiez , Zile Michael R , McMurray John J , Mendelson Michael , Solomon Scott D , Cunningham Jonathan
Published: November 2023

Introduction:
Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined.

Goal:
To identify serum proteins associated with risk for HF hospitalization (HFH) and cardiovascular (CV) death in patients with HFpEF, including proteins with differential associations with clinical outcomes in HFpEF compared to HFrEF.

Methods:
We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF in the PARAGON-HF trial using a modified aptamer proteomic assay. Baseline protein concentrations significantly associated with total HFH and CV death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared to 2515 patients with HFrEF from the PARADIGM-HF and ATMOSPHERE trials.

Results:
We identified 288 proteins to be robustly associated with the risk of HFH and CV death (335 events over an average of 2.7 years of follow-up) in a HFpEF trial population. Proteins most strongly related to HFpEF outcomes included B2M, TIMP1, SERPINA4, and SVEP1 (
Figure
). Protein-outcome associations in patients with HFpEF did not markedly differ compared to HFrEF. Just 3 proteins (APOE, RTF1, and VWF) were differentially associated with outcomes between the HF subtypes (FDR <0.05). A proteomic risk score derived in HFpEF patients was not superior to a previous proteomic score derived in HFrEF nor to clinical risk factors, NT-proBNP, or high-sensitivity cardiac troponin.

Conclusions:
Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis. SVEP1, a cell adhesion protein recently identified as a HFrEF prognosis biomarker, also strongly predicted risk in HFpEF. Our results demonstrate substantial similarities in serum proteomic risk markers across the EF spectrum.
Abstract 13832: XplainScar: Explainable Artificial Intelligence to Identify and Localize Left Ventricular Scar in Hypertrophic Cardiomyopathy (HCM) Using 12-lead Electrocardiogram
Authors: Nezamabadi Kasra , Sivalokanathan Sanjay , Lee Jiwon , Chen Meiling , Lu Daiyin , Mousavi Parvin , Abraham M Roselle
Published: November 2023

Background/Rationale:
Myocardial scar, identified by late gadolinium enhancement (LGE) on MRI, is associated with sudden death in HCM. Unlike ECG, MRI is expensive and adversely affected by artifacts from implanted devices. However, little is known about ECG features of LV-scar in HCM.

Objective:
Develop an ECG-based explainable machine learning method to identify and localize LV-scar in HCM.

Method:
We retrospectively studied 500 HCM patients (JH HCM Registry) for model development, and 248 patients (UCSF HCM Registry) for validation. All patients underwent MRI and ECHO within 1 year of ECG. LV-LGE (scar) was assessed using QMass. After excluding RV-insertion-point-LGE, the LV was divided into basal, mid, and apical regions for scar detection. Resting 12-lead ECGs were segmented, features were extracted and adjusted for LV-mass, age, sex. We utilized unsupervised and self-supervised ECG representation learning, where patients are partitioned into groups of several sub-clusters, each sharing similar ECG patterns, but with high separation between scar and no-scar classes. In each group, a self-supervised neural net and a fully connected neural net successfully predicted LV-scar (see Figure) and revealed ECG features of scar.

Results:
Our method identifies LV-scar in the JH-dataset with high precision (90%), sensitivity (95%), specificity (80%), F1-score (90%), and generalizes well to UCSF-data (precision:88%, sensitivity:90%, specificity:78%, F1-score:89%). The top ECG features for basal-scar are Q-amplitude, Q-slope, non-terminal QRS duration in aVR, and area under QRS and T wave energy in V1-V2. T-wave inversion in V4-V6, area under QRS in V3, TP slope in V3-V4 predicted apical scar. Features selected for mid scar prediction combine features for basal and apical scar.

Conclusion:
This is the first ECG-based ML model to identify/localize LV-scar in HCM. Our model demonstrates good performance and reveals ECG features of scar in HCM.
Abstract 13835: Glutaminolysis Boosts Cardiac Performance Under High Workload via Enhancement of Mitochondrial GSH
Authors: Wang Xinpei , Feng Mengya , Zhang Xing , Li Jia , Gao Feng
Published: November 2023

Introduction:
Glutamine, the most abundant non-essential amino acids in circulation, serves as an important energy source in proliferating cells. Previous evidence has indicated that glutamine is not a primary carbon source for the tricarboxylic acid cycle in cardiomyocytes under physiological workload. However, current clinical studies reveal that impaired glutaminolysis is associated with heart failure and an increased risk of cardiovascular events.

Hypothesis:
We hypothesized that impaired glutaminolysis would compromise cardiac function, especially under conditions of increased workload.

Methods:
We analyzed cardiac structure and function in a mouse model with cardiac-specific knockdown of glutaminase (GLS), a key enzyme of glutaminolysis. Cardiac reserve was assessed by isoproterenol stress echocardiography. We performed transcriptomic,
13
C isotopic labeling, and reactive oxygen species emission analyses to investigate the underlying mechanism.

Results:
GLS deficiency impaired cardiac reserve and exercise capacity in mice, but had no discernible effects on cardiac structure or function under baseline condition. Inhibition of glutaminolysis in pressure-overloaded hearts further exacerbated cardiac dysfunction, indicating the critical role of glutaminolysis in cardiomyocytes under high workload. Mechanistically, glutaminolysis maintained cardiomyocyte function by balancing intracellular redox status through the production of glutathione (GSH), particularly in mitochondria. Inhibition of glutaminolysis decreased both cytosolic and mitochondrial GSH levels, resulting in compromised cell contraction in isolated cardiomyocytes under high workload. Additionally, heterologous expression of an engineered mitochondrial GSH biosynthetic enzyme increased mitochondrial GSH levels and enhanced cardiac reserve in GLS knockout mice.

Conclusions:
Our findings establish the previously unrecognized role of glutaminolysis in cardiomyocytes, maintaining cardiac reserve via upregulating mitochondrial GSH levels. This suggests that targeting glutaminolysis is a potential strategy for improving cardiac reserve and managing cardiac diseases.