bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4139195: Tipping Point Analysis Identifies C-terminal src kinase-Collagen 22 Regulation by Inflammation in the Pathogenesis of Early-Stage Pulmonary Arterial Hypertension
Authors: Wertheim Bradley , Wang Ruisheng , Arons Elena , Oldham William , Alba George , Bowman Frederick , Sharma Nirmal , Haley Kathleen , Samokhin Andriy , Padera Robert , Loscalzo Joseph , Maron Brad
Published: November 2024

Inflammatory injury to pulmonary artery endothelial cells (PAECs) is a key pathogenetic event that drives fibrotic vascular remodeling in pulmonary arterial hypertension (PAH), a progressive disease that lacks early stage-specific therapeutic targets. In an inflammatory rodent model of PAH, we established early-stage disease based on abnormalities in right ventricular (RV) afterload, pulmonary vascular resistance, and RV cardiomyocyte phenotype that were evident without substantial elevation in pulmonary artery pressure. We performed RNA-Seq on PAEC mRNA isolated
ex vivo
from control, early-stage, and advanced-stage PAH rats and deployed a ‘tipping point’ methodology to identify key pulmonary endothelial protein-protein interactions (PPIs) that regulate the transition from control to early-stage PAH
in silico
. Building on prior data on the intersection between glucose and proline signaling in fibrosis, we interrogated our early-stage PAH network for convergent PPIs involving metabolism and fibrosis endotypes. C-terminal src kinase (Csk), a conserved inhibitor of Src, was predicted to regulate PAEC fibrosis and was increased in early-stage PAH. In human PAECs, inflammatory stimuli affected markers of Src activation as well as collagen 22 (Col22A1). We observed that pulmonary arterial Col22A1 expression increased progressively across all PAH stages
in vivo
and that arterial Col22A1 expression is upregulated in human PAH. Further, although inflammation upregulated total Csk mRNA and protein expression in HPAECs, it decreased phosphorylation of Src at tyrosine 527 (pTyr527Src), a Csk-dependent brake on Src kinase activity. Targeting Src through small molecule inhibition or adenovirus overexpression of Csk to increase pTyr527Src, in turn, attenuated inflammation-induced Col22A1
in vitro
. Taken together, these data suggest that acquired inhibition of Csk is a novel molecular mechanism by which inflammation induces pulmonary endothelial dysfunction, Src activation, and fibrosis. In early-stage PAH, disrupted Csk inhibition of Src may induce transcriptional upregulation of Csk as a negative feedback response to Src activation. These data suggest that the Csk-Src-Col22A1 axis is a novel target for advancing early-stage therapeutics in patients with PAH subtypes characterized by inflammatory vascular injury.
Abstract 4139196: Long-term effectiveness and safety of mavacamten in a real-world, multi-center, global study: Preliminary results of COLLIGO-HCM from a diverse cohort in the United States
Authors: Macnamara James , Adler Arnon , Maor Elad , Bastiaenen Rachel , Gold Matthew , Maksabedian Hernandez Ervant , Han Xu , Schuler Patricia , Salazar Joel , Orlandi Paula , Li Leanne , Pichardo Angel , bilen ozlem
Published: November 2024

Introduction:
The mavaCamten ObservationaL evIdence Global cOnsortium in hypertrophic cardiomyopathy (COLLIGO-HCM; ClinicalTrials.gov ID NCT06372457) is a multinational, multicenter observational research initiative aiming to describe the real-world outcomes of mavacamten for the treatment of obstructive HCM.

Aims:
Describe the real-world effectiveness and safety of mavacamten, measured by echo measurements and NYHA class.

Methods:
This retrospective study used data from medical records from two participating HCM centers in the US. Patient-level data was extracted to assess the effectiveness and safety of mavacamten post-treatment initiation through 60 weeks. Patient characteristics and outcomes were described, including echocardiogram measurements, New York Heart Association (NYHA) functional class, and safety.

Results:
A total of 93 patients were treated with mavacamten (mean age 60.6 ± 13.9 years, 23.7% black, 57.0% female, and 77.4% NYHA class III at baseline) with a mean follow-up of 37.0 ± 28.1 weeks (
Table
). From baseline to week 60, 3 (3.2%) patients experienced temporary treatment discontinuation, and 3 (3.2%) discontinued mavacamten due to left ventricular ejection fraction (LVEF) <50%. By week 12, 77.1% of patients had improved by ≥1 NYHA class. The percentage increased to 89.5% by week 24 and remained stable through week 60. Mean changes from baseline in resting and Valsalva left ventricular outflow tract gradients were 31.8 ± 32.8 and 57.3 ± 47.3 mmHg, respectively, at week 24, and remained similar through week 60. Mean change in LVEF from baseline was 4.1 ± 7.1% at week 12 and remained largely unchanged through week 60
(Figure)
.

Conclusions:
This study demonstrated the early and sustained effectiveness of mavacamten with one of the longest follow-ups to date, in a real-world population with a higher racial diversity and disease burden than those in the clinical trials. This data further substantiates the effectiveness and safety profile of mavacamten.
Abstract 4139199: Quantifying the Burden of High Polygenic Risk for Cardiometabolic Disease in a US-based Healthcare System Biobank
Authors: Misra Anika , Truong Buu , Spinks Catherine , Haidermota Sara , Perez Emma , Khurshid Shaan , Bellomo Tiffany , Aragam Krishna , Fahed Akl , Lewis Anna , Hornsby Whitney , Ellinor Patrick , Lebo Matthew , Karlson Elizabeth , Natarajan Pradeep , Patel Aniruddh
Published: November 2024

Background:
Healthcare systems are increasingly collecting genotype data on patients. Polygenic risk scores (PRS), which quantify inherited risk of a given disease, have the potential to leverage this data to identify high risk individuals. While PRS for single traits have often been evaluated, the same data can be used to calculate PRSs across traits and evaluate the overall burden of high cardiometabolic polygenic risk using a single test.

Methods:
We examined the association of cardiometabolic PRS from the Polygenic Score Catalog among 236,393 All of Us (AoU) participants for 6 target traits of interest, using all available PRS for coronary artery disease (CAD; 57 PRS), atrial fibrillation (AF; 30 PRS), heart failure (HF; 9 PRS), type 2 diabetes mellitus (T2DM; 133 PRS), venous thromboembolism (VTE; 9 PRS), and thoracic aortic aneurysm (TAA; 2 PRS). PRSMix is a tool that incorporates information across several PRS for a given trait to improve prediction accuracy for a target population. We generated a PRSMix for each trait and externally benchmarked its performance against individual PRS in the Mass General Brigham Biobank (MGBB). Phenotypes were ascertained using hospital diagnosis and procedural codes. Logistic regression was performed, adjusting for age, sex, and the first 10 principal components of inferred genetic similarity.

Results:
Of the 53,306 genotyped MGBB participants, 55.6% are female, mean enrollment age is 53 ± 17 years. Each trait-specific PRSMix demonstrated generally stronger associations with the target trait compared to any individual contributing score. This included trait-specific PRSMix associations (OR/SD, [95%CI]) of 2.07 [1.99-2.15] for CAD, 1.88 [1.82-1.95] for AF, 1.47 [1.43-1.51] for HF, 2.07 [2.00-2.14] for T2DM, 1.43 [1.39-1.47] for VTE, and 1.40 [1.34-1.46] for TAA. Findings were consistent across inferred genetically similar ancestry groups, with stronger PRSMix associations for CAD detected in the EUR group (2.14 [2.05-2.22]) compared to the AFR group (1.43 [1.21-1.70]). Approximately 37% of people in MGBB have 3-fold greater risk of at least one cardiometabolic disease, with 22% at risk for CAD, 14% for T2DM, 13% for Afib, 3% for VTE, 2% for HF and <1% for TAA.

Conclusion:
We developed PRSMix scores for cardiometabolic traits in AoU and validated them in MGBB. We identified 37% of biobank participants with at least 3-fold greater disease risk associated with high polygenic scores for at least one cardiometabolic outcome.
Abstract 4140100: Outcomes of Percutaneous Coronary Intervention of the Left Main Coronary Artery Bifurcation: Insights from PROGRESS-BIFURCATION registry
Authors: Carvalho Pedro , Strepkos Dimitrios , Rempakos Athanasios , Alexandrou Michaella , Mutlu Deniz , Al-Ogaili Ahmed , Kultursay Barkin , karagoz ali , Krestyaninov Oleg , Khelimskii Dmitrii , Uluganyan Mahmut , soylu korhan , Yildirim Ufuk , Mastrodemos Olga , Rangan Bavana , Jalli Sandeep , Voudris Konstantinos , Burke M Nicholas , Sandoval Yader , Brilakis Emmanouil
Published: November 2024

Background:
There is limited data on the long-term outcomes of percutaneous coronary intervention (PCI) in patients with left main coronary artery (LM) bifurcation lesions.

Methods:
This retrospective, observational, cohort study was performed across 6 centers in the United States, Russia, and Turkey between 2013-2024, as part of the Prospective Global Registry of Percutaneous Coronary Intervention in Bifurcation Lesions (PROGRESS-BIFURCATION, NCT05100992). We examined procedural characteristics and follow-up outcomes of patients with versus without LM bifurcation lesions undergoing PCI. Multivariable adjusted hazard ratios (aHR) with 95% CI were calculated using Cox regression.

Results:
Of 1,089 patients who underwent bifurcation PCI, 289 (26.5%) underwent LM PCI. Patients in the LM group were older (70.1±11.9 vs 65.4±11.5 years; p<0.001) and had more comorbidities, such as diabetes, heart failure, prior PCI, and prior coronary artery bypass graft surgery. Two-stent techniques were more commonly used in LM patients vs. non-LM patients (39.3% vs 26.5%, p<0.001), with similar technical success (94.8% vs 95.9%, p=0.41) and procedural success (93.1% vs 93.1%; p=0.99). The incidence of in-hospital major adverse cardiovascular events (MACE) was higher in LM patients (7.9% vs 4.5%, p=0.04). During long-term follow-up LM PCI patients had higher mortality (aHR 3.17; 95% CI 1.22-8.18; p<0.001), without significant differences in MACE (aHR 1.81; 95% CI 0.93-3.52; p=0.08), myocardial infarction (aHR 0.50; 95% CI 0.07-3.52; p=0.50), and target-vessel PCI revascularization (aHR 2.56; 95% CI 0.75-8.78; p=0.14).

Conclusion:
Follow-up mortality in patients undergoing bifurcation PCI, classified according to whether they underwent left main or non-left main PCI.
Abstract 4140111: Impact of Digital Health Tools on Patients Undergoing Cardiac Rehabilitation
Authors: Tsai Ming-Tse , Dzotsi Marissa , Pazargadi Aryana , Chin Tiffany , Bramwell Jacob , Chang Hao-Chun , Taub Pam
Published: November 2024

Digital health apps are novel tools that have the potential to enhance patient care. However, their benefits in the context of cardiac rehabilitation (CR) are not well studied. This study aims to examine an app’s effectiveness in enhancing exercise performance. The app (KardioPAC) connects to both Bluetooth and cellular-enabled BP devices, which allows providers to monitor and communicate with patients remotely.

We aim to assess the app’s impact on functional capacity (metabolic equivalents /METs) compared to standard of care (SOC) CR.

This study took place at UC San Diego. Participants were recruited from CR, and randomized in a 1:1 ratio to the two study arms (KardioPAC+CR vs SOC CR). The intervention group was requested to take BP at home and upload via KardioPAC. They additionally received a BP reminder daily and got an intra-app call from the care team at least every 1-2 weeks and when needed. All patients, including SOC arm, were asked to complete a pre- and post-CR visit. In each visit, several measurements (including blood pressure, METs, and quality of life questionnaires) were recorded. The study was approved by the UCSD IRB. All statistical analyses were performed on Python 3.11.8.

From Jan 2023 to Mar 2024, 43 patients were enrolled. Table 1 shows their demographics. The mean METs changes are 3.68 vs 2.97 (Intervention vs Control, p=0.052). The mean METs percent changes are 104.39% vs 81.22% (Intervention vs Control, p=0.042), as plotted in Figure 1.

Our study found that digital tools significantly enhance CR patients’ performance, even with a small sample size. Furthermore, we found positive signals of digital tools in reducing patients’ blood pressure and improving their quality of life. Patients’ behavior could be changed by incorporating digital tools into daily practice. Our study warrants large-scale studies to investigate the underlying mechanisms and verify the broader benefits of digital tools, including physical, mental, and social improvements.
Abstract 4140115: Comparison of Lipoprotein(a) and Other Apo B Containing Lipoproteins as Predictors of Major Adverse Cardiovascular Events in ODYSSEY OUTCOMES
Authors: Bittner Vera , Szarek Michael , Steg Philippe , Jukema J , Reijnders Esther , Bhatt Deepak , Diaz Rafael , Fazio Sergio , Garon Genevieve , Goodman Shaun , Harrington Robert , White Harvey , Zeiher Andreas , Cobbaert Christa , Schwartz Gregory
Published: November 2024

Background:
Lipoprotein(a) [Lp(a)] and other atherogenic lipoproteins each contain one molecule of apolipoprotein B (apoB) per particle. Recent studies have suggested that on a per particle basis, Lp(a) is more strongly associated with major adverse cardiovascular events (MACE) than low density lipoprotein.

Hypothesis:
In statin-treated patients with recent acute coronary syndrome (ACS), we tested the hypothesis that, on a per particle basis, Lp(a) and its change on treatment with alirocumab (ALI) are more strongly associated with MACE than other [non-Lp(a)] apoB-containing particles.

Methods:
Molar apolipoprotein(a) [corresponding to Lp(a)] and apo B were measured by mass spectrometry at baseline and month 4 (M4) in a subgroup of 11,957 patients who provided consent for use of stored samples in the ODYSSEY OUTCOMES trial. Non-Lp(a) apoB in nmol/L was calculated as total apo B – Lp(a). Lp(a) and non-Lp(a) apo B at baseline in the placebo group, and absolute changes in their levels on ALI, were related to risk of MACE using proportional hazards models. The latter analysis was adjusted for baseline Lp(a) and non-Lp(a) apo B and stratified by baseline Lp(a) (<125 nmol/L and ≥125 nmol/L).

Results:
Baseline levels of Lp(a) and non-Lp(a) apoB are shown in the
Table
. In the placebo group, both baseline Lp(a) and non-Lp(a) apo B independently predicted MACE. At M4 in the ALI group, median Lp(a) change from baseline was -40.9 and -7.0 in those with baseline levels ≥ or <125 nmol/L, respectively. Corresponding median changes in non-Lp(a) apoB were -739 and -776 nmol/L (all P<0.001). In the ALI group with baseline Lp(a)>125 nmol/L, the decrease from baseline in Lp(a), but not the decrease in non-Lp(a) apo B, was significantly related to risk of MACE. Among those with baseline Lp(a)≤125 nmol/L, the decrease from baseline in non-Lp(a) apo B, but not in Lp(a), with ALI was significantly related to risk of MACE.

Conclusions:
On a per particle basis, baseline Lp(a) and non-Lp(a) apo B both predicted MACE. Among those with high baseline Lp(a), reduction in MACE with ALI was predominantly associated with reduction of Lp(a); among those with lower baseline Lp(a) reduction in MACE with ALI was predominantly associated with reduction in non-Lp(a) apo-B. Lp(a) may be an important target of treatment with ALI in those with elevated levels after ACS.
Abstract 4140117: A novel risk score predicts the prevalence of left atrial low-voltage areas and rhythm outcome in patients undergoing long-standing persistent atrial fibrillation ablation
Authors: Ooka Hirotaka , Matsuda Yasuhiro , Masuda Masaharu , Okamoto Shin , Ishihara Takayuki , Nanto Kiyonori , Tsujimura Takuya , Hata Yosuke , Uematsu Hiroyuki , NAKAO SHO , Kusuda Masaya , Ariyasu Wataru , Kudo Satoshi , Fujii Subaru , Mano Toshiaki
Published: November 2024

Background:
Catheter ablation is a most common treatment for atrial fibrillation (AF), but rhythm outcome after AF ablation in long-standing persistent atrial fibrillation (LS-PerAF) is still poor. Left atrial low-voltage areas (LVAs) is associated with poor rhythm outcome after catheter ablation. However, the predictors of LVAs presence have not been fully elucidated in patients with LS-PerAF.

Purpose:
The purpose of this study was to establish a novel predictive score for the prevalence of LVAs in patients with LS-PerAF ablation.

Methods:
In total, 109 consecutive patients who underwent initial ablation for LS-PerAF were included. LS-PerAF was defined as AF whose duration was more than 1 year. LVA was defined as areas with bipolar peak-to-peak voltage of < 0.50mV. A clinical risk score was obtained as the total number of independent predictors analyzed by multivariate logistic regression analysis. AF recurrence after the catheter ablation was followed for 24 months.

Results:
Of 109 patients with LS-PerAF, LVAs existed in 26 (24%) patients. A novel predictive score, named DESK score, consisted of diabetes mellitus (odds ratio [OR] 3.7, [95% confidence interval {CI} 2.2–11], p = 0.02), age ≥ 70 years (OR 3.8, [95% CI 1.4-10], p = 0.007), female sex (3.0 [95% CI 1.04-8.4], p = 0.04), AF duration ≥ 3.7 years (44 months) (OR 3.7, [95% CI 1.3-11], p =0.02). LVAs were more frequently found in patients with a higher DESK score (OR, 3.5 [95% CI, 1.9–6.5], p < 0.001) (Figure 1A). On receiver operating characteristic curve analysis, DESK score was a moderate predictor of LVAs presence (area under the curve, 0.750; Figure 1B). The optimal cut-off of DESK score was 3 points, corresponding to a 38.5% sensitivity, 97.6% specificity, and 83.5% predictive accuracy. Freedom from AF recurrence was significantly lower in patients with DESK score ≥ 3 than in those with DESK score < 3 (10.4% vs. 43.5%, p = 0.008).

Conclusions:
In patients who underwent LS-PerAF ablation, the DESK score correlated with the prevalence of LVAs, and associated with poor rhythm outcome.
Abstract 4140119: Liver Steatosis and Liver Fibrosis Predict Major Adverse Cardiovascular Events in the CLEAR Outcomes Trial
Authors: de Jong Vivian , Saidi Alina , Castro Cabezas Manuel , Nissen Steven , Sasiela William , Li Na , Bloedon Leanne , Lincoff Abraham , Nicholls Stephen , Grobbee Diederick
Published: November 2024

Background:
Metabolic dysfunction-associated steatotic liver disease (MASLD), and progressive stages accompanied by liver fibrosis (LF), have been associated with liver-related and CV complications in middle-aged patients, although data on the latter is limited.

Objectives:
We evaluated whether liver steatosis (LS) or LF are associated with CV outcomes in a large clinical trial that included patients at high CV risk who were statin intolerant (SI), and if so, whether bempedoic acid (BA) treatment reduces observed increases in CV risk.

Methods:
CLEAR Outcomes evaluated the efficacy of BA in 13,970 SI patients randomized to BA (180 mg daily) or placebo and followed for a median of 40.6 months. The primary outcome was a 4-component major adverse CV event (MACE4: nonfatal MI, nonfatal stroke, coronary revascularization, or CV death). This post-hoc analysis used the following non-invasive algorithms to estimate the presence of LS and LF at baseline: Framingham Steatosis Index (FSI), Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Score (NFS). Continuous variables were reported as mean±SD, categorical variables as proportion. Time-to-event data were analysed using a Cox proportional hazards model. Adjusted hazard ratios (aHR) for every 1 unit increase in score, while holding every other variable constant, and corresponding 95% CI were reported.

Results:
The mean age of included participants was 66±9 years, 48% were female, mean BMI was 30±5 kg/m
2
, and characteristics were balanced over the treatment arms. Baseline FSI was 0.2±1.5, FIB-4 1.3±0.6 and NFS -0.6±1.2. LS was associated with an increased incidence of MACE4 in the whole study population, as indicated by the aHR of 1.09 (1.06-1.12) for 1 unit of FSI increase. LF was also associated with increased risk of MACE4 in the overall population, aHR 1.19 (1.11-1.28) for 1 unit of FIB-4 increase, and aHR 1.14 (1.10-1.19) for 1 unit of NFS increase. For LS, per 1 unit of FSI increase the aHR for MACE4 was lower in the treatment group: aHR of 1.04 (0.99-1.09) for BA vs 1.14 (1.09-1.18) for placebo, interaction p=0.004. For LF, aHR did not differ between groups and no significant interaction with treatment was observed.

Conclusion:
Both LS and LF are associated with an increased risk of MACE4. Overall, BA was associated with lower rates of MACE4 across categories of LS and LF (data not shown). A lower risk of LS-associated MACE4 was observed in the BA group. These benefits are less clear regarding the MACE4 risk driven by LF.
Abstract 4140121: Lipoprotein(a) Local Sybthesis And Plasma Uptake Via MDFS5 in Human Calcified Valve
Authors: Chen Jiaohua , Yang Xinyue , Li Xin , Sun Yinghao , Luo Songyuan , Zheng Shengneng , Li Jie , Luo Jianfang
Published: November 2024

Background:
High circulating levels of lipoprotein(a) [Lp(a)] are associated with increased risk of calcific aortic stenosis (CAS). Targeting Lp(a) metabolism holds promise for therapeutic interventions. However, the precise mechanisms by which Lp(a) accumulates on aortic valves still not fully understood.

Hypothesis:
Lp(a) could be synthesized in situ in human aortic valves under specific stimuli, such as calcification, in addition to being taken up from plasma via membrane receptors, including the newly identified receptor Major Facilitator Superfamily Domain Containing 5 (MFSD5).

Methods:
Immunohistochemistry was used to detect the Lp(a) and its receptor MFSD5 in human aortic valves from CAS patients or controls, which were non-CAS patients. Plasma Lp(a) levels were measured in individuals undergoing aortic valve resection. Human valvular interstitial cells (VICs) were cultured in procalcifying medium, with or without Lp(a) (10uM) for 14 and 21 days. Von-kossa or Alizarin Red staining were used to assess valve calcification. Expression of Lp(a) and MFSD5 was analyzed with quantitative RT-PCR and western blot.

Results:
Lp(a) was nearly absent in control valve site, whereas it was abundantly present in valve site from CAS patients (p＜0.05). The higher the level of Lp(a) detected, the greater the extent of calcification noted in valve site. The mRNA and protein levels of Lp(a) extracted from calcified human valves were significantly higher compared to controls. However, the concentration of plasma Lp(a) did not affect the expression of Lp(a) in valve site (p＞0.05).
In vitro
studies showed that Lp(a) mRNA was minimally detectable in normal VICs, but was significantly upregulated following exposure to procalcifying medium (p < 0.05). Lp(a) incubation led to severer calcification than that induced by procalcifying medium alone (p < 0.05). As MFSD5 was a newly identified receptor of Lp(a), we also test its expression. MDFS5 was increased in human calcified valve (p＜0.05) and calcified VICs (p＜0.05). These results showed that the Lp(a) in valve could be increased by either uptake from serum or by synthesized locally by proper stimuli.

Conclusion:
Our study has shown that the degree of aortic valve calcification is correlated with the level of Lp(a) in the valve site rather than in serum. We also verified MFSD5 was the receptor of Lp(a) on human valve. Targeting Lp(a) accumulation at the valve site may offer a more effective strategy for the prevention or treatment of CAS.
Abstract 4140148: Genetic Influence in Patients Transplanted for Myocarditis in the TOPMed-TOPCHeF Cohort of Explanted Hearts
Authors: Jason Max , Lombardi Raffaella , Graw Sharon , Medo Kristen , Newman Sarah , Bristow Michael , Ambardekar Amrut , Cleveland Joseph , Buttrick Peter , Mestroni Luisa , Taylor Matthew
Published: November 2024

Background:
Myocarditis is a leading cause of secondary cardiomyopathy and stems from infection, medications, or immune etiologies. Recent reports identify an overlap between myocarditis and pathogenic / likely pathogenic (P/LP) genetic variants of dilated and arrhythmogenic cardiomyopathies (DCM/ACM).

Hypothesis:
We hypothesized that myocarditis leading to heart failure and transplantation could be influenced by P/LP mutations for DCM/ACM.

Aims:
To evaluate the impact of genetics in myocarditis, we investigated a series of patients presenting with symptoms consistent with myocarditis who were found to have P/LP genetic signatures for dilated and arrhythmogenic cardiomyopathies DCM/ACM.

Methods:
Patients with myocarditis, defined by retrospective clinical diagnosis, were selected from the NHLBI Trans-Omics for Precision Medicine (TOPMed) - Trans-Omics for Precision Medicine for Congestive Heart Failure (TOPCHeF) cohort. After informed consent, patients’ explanted hearts were collected in the University of Colorado Heart Tissue Bank. A total of 837 hearts (697 failing and 140 control hearts) underwent whole genome DNA sequencing (WGS).

Results:
11 patients had a diagnosis of myocarditis based on clinical history. None had acute myocarditis at time of transplantation. P/LP variants in DCM/ACM genes were found in 6 patients. The average age at transplantation was 42.8 years for patients with genetic variants and 38.9 without. Demographics are included in table 1. The most common genetic variants were Titin truncations. Full genetic data are included in table 2.

Conclusion:
50% of patients undergoing transplantation with a clinical diagnosis of myocarditis in the TOPMed-TOPCHeF population had P/LP variants in DCM/ACM genes. This underscores the importance of genetic testing in patients with a clinical presentation of myocarditis for future management implications.
Abstract 4140151: Network Analysis of Differentially Expressed Genes after Silencing Dynamin 2 in Pulmonary Arterial Hypertension
Authors: Wu Danchen , Das Gupta Asish , Chen Kuang-Hueih , Hindmarch Charles , Hu Ting , Archer Stephen
Published: November 2024

Rationale:
Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disease that can cause right heart failure and even death. In PAH, excessive mitochondrial fission is responsible for the hyperproliferation of pulmonary artery smooth muscle cells (PASMC), which is incompletely mediated by the large GTPase dynamin-related protein 1 (Drp1). We hypothesize that another GTPase, Dynamin 2 (DNM2), elevated in PASMC of PAH patients, is responsible for the final stage of mitochondrial fission.

Objectives:
1. Identify the differentially expressed gene (DEG) signature in PAH PASMC after silencing DNM2 using small interfering RNA (siRNA) by means of RNA sequencing (RNA-seq); 2. Identify the biological processes or pathways associated with these DEGs.

Methods:
Human PAH PASMCs (n=5 cell line) were transfected with control siRNA or siRNA targeting DNM2. 3’RNA-seq was used to create libraries which we sequenced on the Illumina Nextseq550. Bioinformatic analysis revealed DEGs which we placed into context using the STRING: protein query database and visualized using Cytoscape 3.10.2. Network functional enrichment analysis was performed using STRING.

Results:
Inhibiting DNM2 significantly reduced mitochondrial fission and slowed PAH PASMC proliferation. RNA-seq identified 156 DEGs (80 down-regulated, 56 up-regulated). The top 5 down-regulated DEGs were
DNM2
,
RGCC
,
TICAM1
,
RASSF3
,
MRPL39
and the top 5 up-regulated DEGs were
ITIF1
,
ARL6IP1
,
POLR3G
,
CBX1
,
CMPK2
. We tested the biologic relevance of
RGCC
which encodes the Regulator of Cell Cycle using siRNA and showed inhibition of cell proliferation in human PAH PASMC. Network analysis identified 152 edges amongst all DEGs. The largest subnetwork contains 77 nodes and 151 edges.
PXDN
, which encodes Peroxidasin, a heme-containing peroxidase that is secreted into the extracellular matrix, has the highest degree of connectivity (15 connections), the highest betweenness centrality (0.266), and the highest closeness centrality (0.441). Enrichment analysis found that the p53 signaling pathway and the cytokine signaling in the immune system are the top KEGG and Reactome pathways affected by siDNM2, respectively.

Conclusions:
DNM2 appears to be an important regulator of the increased mitochondrial fission in PAH. Silencing DNM2 not only inhibits fission but also slows cell proliferation, apparently by reducing the expression of RGCC. Silencing DNM2 in human PAH PASMC results in the disruption of 136 genes.
Abstract 4140168: Association of left and right branch blocks with clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF)
Authors: Reddy Sukhila , Singh Vishwajeet , Dwivedi Alok , Mukherjee Debabrata , deoker abhizith
Published: November 2024

Background:
Although left (LBBB) and right (RBBB) bundle branch blocks play a critical role in cardiovascular pathogenesis, the associations of LBBB and RBBB with cardiovascular (CV) outcomes, especially in patients with HFpEF is understudied compared with normal QRS.

Aim:
We assessed clinical outcomes of LBBB and RBBB in patients with HFpEF who were admitted for acute decompensated heart failure compared with those without bundle branch blocks.

Method:
A cross-sectional study was conducted using the National Inpatient Sample (NIS) database from 2019. We only included adult hospitalizations with HFpEF admitted for acute decompensated heart failure in the study. Hospitalized records were categorized into three groups (LBBB, or RBBB, and those with normal QRS). Clinical outcomes included atrial fibrillation (AF), ventricular fibrillation (VF), complete heart block (CHB), sick sinus rhythm (SSR), cardiac arrest (CA), length of stay (LOS) and in-hospital mortality. Propensity score (PS) inverse probability of treatment weighting and matching were applied to determine the association between BBB types and CV outcomes and validated associations in sensitivity analyses.

Results:
A total of 334511 hospitalizations with HFpEF included LBBB (6818, 2%) and RBBB (7948, 2.4%) were analyzed. Compared to normal QRS, LBBB was associated with VF (odds ratio [OR]=2.47, p<0.001), SSR (OR=1.72, p<0.001), CHB (OR=2.77, p<0.001) and longer LOS (relative risk [RR]=1.15, p<0.001) after adjusting for covariates in PS analysis. Similarly, RBBB was associated with AF (OR=1.30, p<0.001), VF (OR=1.59, p=0.033), SSR (OR=1.72, p<0.001), CHB (OR=2.81, p<0.001), CA (OR=1.19, p<0.001), and longer LOS (RR=1.08, p<0.001) [Table 1]. These associations remained consistent in multiple validation analyses including after additionally adjusting for obesity, hypertension and diabetes.

Conclusion:
In hospitalized records with acute decompensated HFpEF, BBB was associated with increased risk of CV outcomes and longer hospital length of stay. The extent of association with multiple CV outcomes varied according to RBBB and LBBB.
Abstract 4140180: The Effect of Benzodiazepine Use in Patients with Atrial Fibrillation and Obstructive Sleep Apnea
Authors: Abi-Rached Joe , bidaoui ghassan , Tsakiris Eli , Feng Han , Liu Yingshuo , Younes Hadi , Assaf Ala' , Bsoul Mayana , Tirado Polo Francisco , Jia Yishi , Lim Chanho , Gu Yuxuan , Pandey Amitabh , Rao Swati , donnellan eoin , Kreidieh Omar , Marrouche Nassir
Published: November 2024

Introduction:
Sleep apnea is a common sleep disorder that can worsen atrial fibrillation(AF) prognosis. Benzodiazepines(BZD) are commonly prescribed for insomnia, which often accompanies sleep apnea. However, BZDs have been associated with worsening of sleep apnea due to respiratory depression, pharyngeal muscle relaxation, and increase of arousal threshold, which all may lead to prolonged hypoxia. There is little research on the effect of BZD use in AF patients with sleep apnea. Therefore, the objective of this study is to investigate the effects of BZD usage on outcomes in the AF population with sleep apnea.

Methods:
Data from patients with AF and sleep apnea seen at Tulane Medical Center between 2010 and 2019 was obtained from Research Action for Health Network(REACHnet), a Clinical Research Network in PCORnet®. Patients with AF and sleep apnea were divided between those with a prescription of BZD and those without BZD. These two groups were compared using the Kaplan-Meier method for time-to outcome for all-cause mortality, ischemic stroke, myocardial infarction(MI), and hospitalizations in the five years following their AF diagnosis. Cox regression analysis was used to investigate proportional hazards and control for demographics, comorbidities, and medication use.

Results:
There were 524 total patients included with AF and sleep apnea. Of these, 413(78.8%) were not prescribed BZDs, while 111(21.1%) were taking BZDs. Use of BZDs was associated with worse outcomes. In the no BZD and the BZD group over the 5 years following AF diagnosis, the rate of mortality was 6.1% and 12.6%(p<.001), the rate of ischemic stroke was 16% and 23.4%(p=.008), the rate of MI was 11.9% and 22.5%(p<.001), and the rate of hospitalization was 51.8% and 59.5%(p<.001), respectively. In multivariate Cox regression, use of BZD was associated with higher mortality(HR: 2.65; CI: 2.26-3.05; p=.013) and hospitalization(HR: 2.15; CI: 1.99-2.31;p<.001).

Conclusion:
BZD use was associated with an over 2-fold increase in all-cause mortality and hospitalizations in patients with AF and sleep apnea. This suggests that BZDs should be used with caution in this patient population, and other treatment modalities for insomnia should be considered.
Abstract 4140181: Mechanisms of SGLT-2 Inhibitor Empagliflozin in Attenuating Intramitochondrial Stress and Restoring Mitochondrial Function in Hyperglycemic Cardiomyocyte
Authors: Lin Chen-Hsuan , Lin Yi-hsiung , Liu I-Hsin , Lin Tsung-Hsien , Jhuo Shih-jie
Published: November 2024

Systemic hyperglycemia causes tissue damage and triggers cardiovascular disease (CVD). Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are a novel class of glucose-lowering agents that have shown unexpected benefits in clinical trials for the treatment of CVDs. We aim to investigate the underlying mechanisms of how SGLT-2 inhibitors alleviate CVDs associated with elevated glucose stress. iPSC-derived cardiomyocytes (iPSC-CM) were incubated with high glucose concentrations for 72 hours. Mitochondrial function in these cardiomyocytes was assessed by flow cytometry with JC-1 staining and ATP luminescence assay. Intracellular reactive oxygen species (ROS) and intramitochondrial calcium stress were measured using CellROX, MitoSOX, and Rhod-2 AM staining. Patch clamp was employed to determine ion current changes in the cardiomyocytes. Mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were determined using the Seahorse XFe96 analyzer. In addition, qPCR, Western blot, and DM mouse heart histological analysis were performed to assess the regulation of associated molecules. The results indicated that exposure to a high glucose environment caused cardiomyocyte injury and impaired mitochondrial biosynthesis. Empagliflozin exhibited a beneficial effect on mitochondrial function by reducing ROS production and calcium deposition. It also mitigated the reduction in respiratory OCR of cardiomyocytes induced by high glucose incubation. Furthermore, molecular analysis revealed that Empagliflozin attenuated the dysregulation of mitochondrial calcium channels and biosynthesis by reducing associated gene expression, including
Bcl2
,
Mfn1
,
Mx2
,
Oas1
,
Ant3
,
Mcu
,
Micu1
,
Vdac1
,
Ryr2
, and
Cypd-ppid
. Histological analysis of DM mouse hearts demonstrated that reduced MFN2 and ZBP1 were target molecules for hyperglycemia-induced reduction of calcium channel currents in cardiomyocytes and could be restored by Empagliflozin treatment. This study concludes that high glucose stress diminishes mitochondrial calcium channel regulators MFN2 and ZBP1 in cardiomyocyte, which reduces calcium channel currents and leads to sensitization of cardiomyocyte to arrhythmogenesis, resulting in VT/VF. It provides experimental evidence for the clinical efficacy of Empagliflozin in ameliorating CVDs and managing diabetes-related CVDs.
Abstract 4141437: Identification of Mitochondrial-related Diagnostic Biomarkers of Acute Type A Aortic Dissection and Pan-Cancer Analysis
Authors: Tan Fangshun , jiang yu , yu miao , Qian Hai-Yan , Yang WeiXian
Published: November 2024

Background:
Acute Type A Aortic Dissection (ATAAD) is a lethal disease with limited predictability globally. Cancer, a severe public health issue worldwide, has now become the second leading cause of death in America. In this study, we aimed to explore potential common mechanisms and therapeutic targets between ATAAD and cancer.

Aims:
Identify mitochondrial-related diagnostic biomarkers of ATAAD and their roles in various cancers.

Methods:
ATAAD-related datasets GSE52093, GSE98770, GSE190635 were downloaded from GEO and merged after removing batch effects. We verified 119 mitochondrial-related differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Using five machine learning methods (LASSO, SVM, Decision Tree, Random Forest, and Boruta algorithm), we identified two mitochondrial-related diagnostic biomarkers of ATAAD: PPIF and CASQ1. The diagnostic accuracy was performed using receiver operating characteristic (ROC) curves. RT-qPCR was used to detect PPIF and CASQ1 expression. Immune infiltration analysis suggested that PPIF may play a key role in tumor immune microenvironment. We utilized TCGA and GTEx databases, Kaplan-Meier analyses and Cox regression analyses to assess PPIF expression and survival analysis in 33 cancer types. qPCR and Western Blot (WB) assays verified PPIF overexpression in lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC). CCK-8, wound-healing and transwell assays further verified PPIF’s proliferative, migratory and invasive abilities in LUAD and UCEC.

Results:
Our study identified PPIF and CASQ1 as hub mitochondrial-related diagnostic biomarkers of ATAAD. Besides its close association with tumor immune infiltration, PPIF also overexpressed in multiple cancer types. Survival analysis suggested the prognostic value of PPIF in most cancers. Experimental results further verified that PPIF promotes the proliferation, migration, and invasion of LUAD and UCEC.

Conclusions:
PPIF and CASQ1 are potential mitochondrial-related diagnostic biomarkers of ATAAD, not previously reported. Pan-cancer analysis implies that PPIF may serve as a key prognostic and therapeutic target in multiple cancers. PPIF may act as a hub gene linking ATAAD and cancer, offering new insights to reduce ATAAD incidence in cancer patients.
Abstract 4141439: Catheter ablation and clinical outcomes among older Medicare beneficiaries with atrial fibrillation
Authors: Hsu Benjumin , Kim Dae
Published: November 2024

Background:
Catheter ablation (CA) is increasingly used for treatment of atrial fibrillation (AF). However, CA has not been widely adopted in the older population with AF. The aim of this study is to examine the risks of adverse outcomes following CA in older people with AF.

Methods:
Using 2014-2019 Medicare claims, we conducted a propensity score analysis of patients treated with CA within 6 months of new AF diagnosis to patients treated with only antiarrhythmic therapy in the 6-month period. The outcome follow-up began after the 6-month period. Cox proportional hazards models were used to estimate hazard ratios (HR) for the composite and individual endpoints from CABANA trial (death, stroke, major bleeding or cardiac arrest) and CASTLE-AF trial (death or heart failure). Subgroup analyses were performed by sex, race-ethnicity, social deprivation index, frailty and dementia.

Results:
The study population comprised of 14623 AF patients (mean age, 76.1±7.6 years; 55% female, 28% frailty, 13% dementia), including 8% receiving CA. The mean follow-up was 1.8 years. Compared to patients with only antiarrhythmic therapy, patients treated with CA had lower rates of CABANA endpoints (CA vs antiarrhythmic therapy: 5.6 vs 11.7 per 100 person-years; HR:0.72, 95%CI:0.66-0.77) and CASTLE-AF endpoints (6.5 vs 13.8 per 100 person-years; HR:0.72, 95%CI:0.67-0.78). The benefits of CA were consistent in both female and male for CABANA endpoints (female: HR:0.71, 95%CI:0.64-0.79 and male: HR:0.72, 95%CI:0.65-0.81) and CASTLE-AF endpoints (female: HR:0.65, 95%CI:0.59-0.73 and male: HR:0.78, 95%CI:0.71-0.87), and in both frail and non-frail patients for CABANA endpoints (frail: HR:0.72, 95%CI:0.66-0.80 and non-frail: HR:0.70, 95%CI:0.63-0.77) and CASTLE-AF endpoints (frail: HR:0.89, 95%CI:0.81-0.97 and non-frail: HR:0.69, 95%CI:0.63-0.75). Similar trends were observed for subgroups defined by race-ethnicity, social deprivation index, and dementia.

Conclusions:
These findings suggest that CA may be beneficial for older AF patients. Nonetheless, further investigation of the safety and efficacy of CA given to older patients in well-designed interventional trials are warranted.
Abstract 4141448: Evaluation of cardiac amyloidosis with cardiac MRI and association with endomyocardial biopsy findings
Authors: Huerta Nicholas , Khalid Taha , Bene-Alhasan Yakubu , Pingili Adhvithi , Woldu Bethel
Published: November 2024

Introduction:
Late gadolinium enhancement (LGE) observed on cardiac magnetic resonance imaging (CMR) has emerged as a potential indicator of myocardial involvement in cardiac amyloidosis (CA). However, discerning which LGE patterns in amyloidosis distinguish it from other cardiomyopathies remains unclear. This study aims to compare LGE characteristics in a predominantly African American cohort who underwent endomyocardial biopsies. Despite advancements in cardiac imaging techniques, the endomyocardial biopsy remains the gold standard for amyloidosis diagnosis. Insights garnered from this analysis could enhance diagnostic precision and facilitate earlier detection.

Methods:
In this retrospective study at MedStar Union Memorial Hospital in Baltimore, MD, patients who underwent both endomyocardial biopsy and CMR were included. The study compared individuals with biopsy-proven amyloidosis (both AL and ATTR) to those with negative biopsy results. LGE patterns were selected based on their frequent use in CMR interpretation. Statistical analysis employed Pearson chi-square and t-tests.

Results:
The cohort comprised 42 patients who underwent biopsy, with 13 patients (31%) with positive biopsy results. Among them, 24 were men (57%), and 81% identified as African American. Demographic, anthropomorphic, and objective clinical findings are detailed in Table 1. The average age of the cohort was 68 years, with those with biopsy-proven amyloidosis significantly older (75 vs. 61 years, p = 0.002). Although the biopsy-positive group exhibited a lower absolute NT-pro-BNP, the difference was not statistically significant. The most prevalent LGE patterns among the biopsy-positive group were diffuse (62%) and basal (31%). Notably, 69% of biopsy-positive patients exhibited an LGE pattern described as infiltrative. However, 38% of the biopsy-negative group also manifested infiltrative patterns on LGE, a difference not statistically significant compared to the biopsy-positive group. The positive predictive value of an infiltrative LGE pattern was low (45%).

Conclusion:
This study compares CMR LGE patterns in biopsy proven CA. Despite findings of an infiltrative LGE pattern on CMR, when using endomyocardial biopsy as the gold standard, the positive predictive value of LGE in differentiating CA patients was low. Further research and larger studies are warranted to explore additional imaging modalities or biomarkers that may complement or refine the diagnostic algorithm for CA.
Abstract 4141453: The Pandemic influenced the Self-care of African Immigrants with Diabetes and Hypertension
Authors: Osokpo Onome , Adeniji Dolapo O , Bracy Danny , Lewis Lisa , Riegel Barbara
Published: November 2024

Background:
Self-Care is essential for chronic illness management. Self-Care comprises three domains: Self-Care maintenance (daily behaviors to maintain health [e.g., medication adherence]), Self-Care monitoring (surveillance for changes), and (3) Self-Care management (prompt response to symptoms). The COVID-19 pandemic challenged self-care in some populations, but little is known about how it influenced the self-care of African immigrants living in the US with chronic illnesses such as hypertension and diabetes.

Methods:
Using a qualitative descriptive design, we enrolled a purposeful sample of 24 sub-Saharan African immigrant adults with self-reported symptomatic hypertension or diabetes. Participants who spoke English were enrolled between March 2020 and September 2021. Individual audio-taped interviews were transcribed and analyzed. Inductive and deductive thematic analysis was guided by the Theory of Self-Care of Chronic Illness.

Results:
Participants were mean=59 years (range 40-72). Most were Nigerian (n=16), male (n=16), married (n=17), living with family (n=21), highly educated (n=21), and reporting enough income to meet their needs (n=21). Five major themes were identified: (1) Being especially careful in following COVID-19 precautions (e.g., use of facemasks). (2) A focus on self-care maintenance (e.g., healthy diet, staying active while at home). Fear of COVID-19 increased medication adherence. Participants were diligent in taking medications as prescribed due to fear of COVID-19. (3) Close monitoring for symptoms. (4) Trouble reaching providers to discuss symptoms. (5) Access to resources. Participants reported loss of health insurance/jobs and lack of provider access, which impacted their ability to perform self-care.

Conclusions:
COVID-19 increased focused attention on self-care but also created barriers for sub-Saharan African Immigrants. Most impacted was self-care maintenance. Interventions to promote self-care in this population should leverage heightened vigilance to self-care and address challenges around access to resources.