bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4143839: Irregular Sleep Duration is Associated with Altered 24-Hour Heart Rate Profile in Patients Enrolled in Cardiac Rehabilitation
Authors: Covassin Naima , Maiti Dolly , Ortega Aviles Laura , mansukhani meghna , Lopez-Jimenez Francisco , Somers Virend , Bonikowske Amanda
Published: November 2024

Introduction:
Sleep duration is now recognized as an important determinant of cardiovascular (CV) health. Recently, the CV implications of day-to-day variability in sleep duration have become apparent, with irregular sleep duration associated with increased risk of CV disease, including hypertension. However, the relationship between sleep duration variability and ambulatory blood pressure (BP) patterns in the general population or in patients with CV disease is unknown.

Research Questions:
We sought to investigate whether irregular sleep duration is associated with aberrant ambulatory BP or heart rate (HR) profiles in patients undergoing cardiac rehabilitation (CR).

Methods:
We recruited a sample of 42 patients with coronary artery disease enrolled in CR at Mayo Clinic Rochester. Participants underwent 24-hour ambulatory BP monitoring and sleep assessment including one week of wrist actigraphy and sleep diary prior to entering CR. Twenty-four hour, awake, and asleep averages were calculated for systolic BP, diastolic BP, and HR. Nocturnal dipping and morning surge were also computed for BP and HR. Sleep regularity was quantified by SD of actigraphy-derived sleep duration and irregular sleep duration was defined as SD >1 hour. Chi-square tests and Mann-Whitney U tests were used to compare groups.

Results:
Thirty-six participants (22% females, median age [25
th
,75
th
IQR] 66.5 [61,75.8] years, body mass index 31.7 [26.9,35.1] kg/m
2
) had valid actigraphy and ambulatory BP recordings. We found sleep duration SD >1 hour in 36% of them. Demographics and average sleep duration were similar between those with irregular and regular sleep duration (all Ps>0.11). Twenty-four-hour, awake and asleep HR values were comparable between groups (all Ps>0.26). Participants with irregular sleep duration exhibited lower nocturnal HR dipping (9.2 [3.1,11.6] % vs 12.9 [8.9,18.2] %, P=0.019) than their counterparts with regular sleep. Morning HR surge was also attenuated in patients with irregular sleep duration (3 [-1,9] bpm vs 10 [7,14] bpm, P=0.006). Ambulatory SBP and DBP measures did not differ significantly between groups (all Ps>0.17).

Conclusions:
High day-to-day variability in sleep duration is linked to blunted nocturnal dipping and morning surge in HR in patients with coronary artery disease enrolled in CR. Because altered ambulatory HR profile predicts unfavorable CV outcomes, evaluation of sleep patterns in the CR setting may yield important prognostic information.
Abstract 4143847: CRISPR screening identifies critical factors regulating DNA damage response in human cardiomyocytes under oxidative stress
Authors: Kubota Masayuki , Ito Masamichi , Nomura Seitaro , Takeda Norihiko , Komuro Issei
Published: November 2024

Introduction:
Our previous studies have shown that sustained activation of the DNA damage response (DDR) in cardiomyocytes leads to p53/p21 activation and cardiac dysfunction. Although the DDR generally involves molecules in DNA replication and repair pathways, the non-proliferative nature of cardiomyocytes suggests a cardio-specific DDR mechanism. However, our understanding of DDR in cardiomyocytes remains limited. Here, we aim to use CRISPR interference (CRISPRi) knockdown screens to identify genes critically involved in DDR regulation in human cardiomyocytes. We hypothesize that identifying these gene clusters may allow us to develop methods to prevent cardiac dysfunction by suppressing DDR in cardiomyocytes.

Methods and Results:
We established a human iPS cell line stably expressing dCas9-KRAB, which allows CRISPRi-mediated gene knockdown, and differentiated the cells into cardiomyocytes. The resulting human iPS cell-derived cardiomyocytes (hiPSCMs) showed the achievement of approximately 80% knockdown efficiency after gRNA transfection. We stimulated the hiPSCMs with H
2
O
2
and quantitatively evaluated the expression levels of the DDR markers γH2AX and p21 by immunostaining using the Operetta
®
high content imaging system. The DDR markers showed a significant concentration-dependent increase in response to H
2
O
2
administration. For arrayed CRISPRi screening, we constructed a gRNA library targeting 437 DDR-related genes. Using this library, we knocked down each DDR-related gene in hiPSCMs followed by H
2
O
2
stimulation. We quantified the expression levels of DDR markers by calculating the fluorescence intensity ratios relative to control after gene knockdown, and standardized them to calculate Z scores for all 437 genes. The screening successfully revealed the differential impact of each gene knockdown on γH2AX and p21 expression. We identified 71 genes that significantly affected their expression (Z-score < -1 or > 1). Mapping these genes to DDR pathways highlighted the differential impact of gene knockdown within the same pathway, and stratified their importance in cardiomyocytes.

Conclusions:
Arrayed CRISPR screening using hiPSCMs revealed differential functional significance of DDR-related genes in cardiomyocytes, identifying 71 genes of particularly significant importance. These findings provide a critical understanding of the cardio-specific DDR pathway and important clues for establishing an appropriate method to suppress DDR in the failing heart.
Abstract 4143866: The Effect of S100A6 Gene Therapy on Cardiac Function in a Rat Model of Ischemic Cardiomyopathy
Authors: Gholami Chookalaei Leila , Tsoporis James , Kuliszewski Michael , Leong-Poi Howard
Published: November 2024

Background:
S100A6 is a small calcium-binding protein that is important in managing calcium storage and myocyte contractility. This protein has a low basal cardiac expression and is upregulated following Myocardial Infarction (MI). Previous experiments have demonstrated that S100A6 gene transfer improves left ventricular function after acute ischemia/reperfusion injury.

Hypothesis: Delivery of S100A6 by Ultrasound-Targeted Microbubble Destruction (UTMD) after established MI model results in improved left ventricular function and prevention of adverse ventricular remodeling.

Aim:
Assess the impact of UTMD delivery of S100A6 on cardiac function following experimental MI.

Methods:
MI was induced through permanent left anterior descending (LAD) coronary artery ligation in 8-week-Spragues Dawley (SD) male rats on day 0. On day 28, by using UTMD methods, we delivered microbubbles (1×109) coupled with either 200 μg of human S100A6 mini-circle DNA or empty minicircles to the left ventricle (LV), while control animals received no therapy. The three groups were monitored weekly for four weeks post-gene delivery using serial echocardiography to follow LV function, followed by tissue collection from various regions of the myocardium.

Results:
At day 28 post-MI, all groups showed reduced LV ejection fraction (LVEF) and fractional shortening (FS), with LVEF and FS values of 39.47±1.49% and 19.75±2.38%, respectively. Meanwhile, healthy animals showed LVEF and FS values of (63.75±2.38% and 36.20±1.29% (p<0.001). Four weeks after the UTMD delivery of the S100A6, LVEF increased to 51.14±3.7% and FS increased to 29.66±3.2% (p<0.05). In contrast, the empty minicircle and control groups showed no significant improvement (38.35±2.6% and 20.66±5.2%, p<0.05). The S100A6-treated group at 28 days post-treatment showed a 2.7±1.2-fold increase in the expression level of S100A6 in the border zones. Interestingly, the peri-infarct zone of S100A6-treated myocardium also had a lower expression level of the hypertrophic marker, β-MHC (0.77±0.7-fold), as compared to those of the control groups (2.48±1.63-fold). S100A6 transfection reduced infarct size (24.75±3.3%); vs control (36±4.58%), p<0.05 and decreased collagen content in viable myocardium compared to the control and empty minicircle group, p<0.01.

Conclusion:
S100A6 overexpression in the peri-infarct zone decreased both hypertrophy and fibrosis and was beneficial to the preservation of cardiac function in a model of chronic MI.
Abstract 4143869: Leveraging ACHD Patients’ Perceptions of Their Illness to Enhance Patient Engagement and Tailor Provider Care Recommendations
Authors: Macholl Katelyn , okumura megumi , Buenrostro Karina , Mehta Juhi , Sparks Aleah , Ahuja Pranav , Sun Kevin , Dohan Daniel , Gurvitz Michelle , Agarwal Anushree
Published: November 2024

Introduction:
Previous research has described barriers and facilitators for adherence to care guidelines among adults with congenital heart disease (CHD). However, uncertainty remains on how to best support patients in clinical practice within time and resource constraints.

Aim:
To examine how patients incorporate CHD into their identity and how that influences the management of their condition.

Methods:
We conducted 48 semi-structured qualitative interviews with adult CHD patients and providers (cardiologists, nurses, patient coordinators, and social workers). Purposive sampling was used to gain patient diversity in CHD lesions, race/ethnicity, SES, geography, and prior gaps in care. Interviews were conducted by a single interviewer using a semi-structured guide based on the “Capability, Opportunity, Motivation-Behavioral (COM-B)” Framework to explore perceived determinants of behavior for managing CHD and navigating the adult health system. Rapid qualitative analysis was conducted to develop two structured data matrices displaying themes about the influence of CHD on identity and enablers of patient engagement.

Results:
Of 31 patients, 39% were male, 58% were People of Color, and 35% had prior gaps in care (of 3 or more years). Five domains (from 15 themes) emerged to characterize how patients viewed CHD as influencing their ability to engage with care. Themes included 4 Illness Identity domains (Rejection, Acceptance, Engulfment, and Enrichment) and a fifth domain of Indifference - characterized by a lack of emotional valence that accompanies the other four domains. Variance in these domains could be tracked to differences in patient outcomes, such as perceived ability to navigate the healthcare system (Figure 1). Providers and patients demonstrated concordance regarding the perceived influence of illness domains on patients’ mental health but less concordance regarding its impact on patient engagement and healthcare navigation.

Conclusion:
Considering the extent to which a patient views their CHD as a component of their identity could help providers support adult CHD patient engagement, tailor counseling about care guidelines, and likely enhance the effectiveness of patient-provider relationships.
Abstract 4143905: Distribution of Coronary Artery Plaque Volume by Artificial Intelligence Quantitative Coronary CT Angiography in General Population: Results from the Miami Heart Study
Authors: Ichikawa Keishi , Bishay Rachelle , Krishnan Srikanth , Benzing Travis , Kianoush Sina , Aldana Jairo , Cainzos Miguel , Feldman Theodore , Fialkow Jonathan , Nasir Khurram , Budoff Matthew , Ronen Shai
Published: November 2024

Background:
Coronary computed tomography angiography -derived plaque burden is associated with the risk of cardiovascular events and is expected to be utilized in clinical practice. Understanding of CT quantitative plaque volume compares to normative values in the general population is clinically important for determining management. This study aimed to investigate the distribution of coronary artery plaque volume in general population and to develop nomographic quantitative plaque volume using the Miami Heart Study, a large community-based cohort study.

Methods:
A total of 2,301 asymptomatic subjects without coronary artery disease (CAD) enrolled in the Miami Heart Study were included. Quantitative assessments of atherosclerotic plaque volume (total, calcified, and non-calcified plaque) were performed using artificial intelligence-guided quantitative coronary computed tomography angiography analysis (AI-QCT). The percentiles of the plaque distribution by gender and age were estimated with nonparametric techniques.

Results:
The mean age was 53.5 years and 50.4% were male. The majority of study participants were Hispanic/Latino (47.2%) and White (85.5%). In terms of traditional risk factors, approximately one-third of the cohort were current or former smokers, 4.3% had diabetes, 24.9% had hypertension, and 34.9% had high cholesterol or lipid abnormalities. Overall, 93.1% of men and 84.6% of women had any plaque using AI-QCT. The median total plaque volume was 54 mm
3
(IQR 16-126 mm
3
) and increased with age. Male subjects had more median total plaque volume, calcified plaque volume, and noncalcified plaque volume than female subjects (80 mm
3
vs 34mm
3
, 4 mm
3
vs 2 mm
3
, and 66 mm
3
vs 27 mm
3
, respectively). Younger individuals tend to have a higher percentage of noncalcified plaque.

Conclusions:
In this asymptomatic population without known CAD, 93.1% of men and 84.6% of women had CAD detected using AI-QCT. Additionally, we developed age- and sex-specific nomograms for atherosclerotic plaque volume. Our data enhance the understanding of plaque volume distribution in general population and should be an important indicator in clinical practice.
Abstract 4143907: Immediate versus staged percutaneous coronary intervention of non-culprit lesions in patients with st-elevation myocardial infarction and multivessel disease: a meta-analysis of 4,120 patients.
Authors: Paulino Daniel , Andrade Arbaiza Edwin , Navarro Martinez Daniel , Xiloj Shirley , Hernandez Bruno , Garcia-Mena Lissette
Published: November 2024

Introduction:
Multivessel coronary artery disease is common in patients with ST-segment elevation myocardial infarction (STEMI). Previous trials have shown that comprehensive revascularization of non-culprit arteries with significant stenosis reduces the risks of cardiovascular death, myocardial infarction, and ischemia-driven revascularization compared to culprit-only revascularization. However, the optimal timing for revascularizing non-culprit lesions—immediate versus staged percutaneous coronary intervention (PCI)—remains unclear. This meta-analysis aims to determine if staged or immediate PCI is associated with fewer major adverse cardiovascular events.

Methods:
A meta-analysis was conducted following PRISMA guidelines, with a protocol registered in PROSPERO (CRD42023485163). We included studies from PubMed, Embase, and Cochrane databases until October 10, 2023. Inclusion criteria were: 1) patients over 18 with STEMI and hemodynamically stable multivessel disease; 2) intervention: immediate PCI; 3) comparator: staged PCI; 4) study types: randomized clinical trials (RCTs) and cohort studies. Study quality was assessed using ROBINS-I for observational studies and ROB 2 for RCTs.

Results:
Nine studies met inclusion criteria: 3 RCTs and 6 cohort studies, with a total of 4,120 patients. Staged PCI was significantly associated with reduced cardiovascular death (RR = 1.77; 95% CI = 1.11-2.81; p = 0.02, I
2
= 24%) and all-cause mortality (RR = 1.83; 95% CI = 1.19-2.79; p = 0.005, I
2
= 42%). Hazard ratio analysis also favored staged PCI for cardiovascular death (HR = 4.11; 95% CI = 1.07-5.87; p = 0.04, I
2
= 12%) and all-cause mortality (HR = 8.13; 95% CI = 1.01-8.17; p = 0.05, I
2
= 37%). No significant differences were found for major adverse cardiovascular events (RR = 0.98; 95% CI = 0.74-1.28; p = 0.86, I
2
= 53%) or in major bleeding, stroke, or target vessel revascularization.

Conclusion:
In patients with STEMI and multivessel disease, staged coronary revascularization is associated with a lower risk of major adverse cardiovascular events, cardiovascular death, and all-cause mortality compared to immediate revascularization, without increasing adverse outcomes. Further research is needed to confirm these findings.
Abstract 4143909: Ectopic Fat Distribution and Adverse Muscle Composition in South Asians: Findings from the UK Biobank
Authors: Tejani Sanaa , Linge Jennifer , Neeland Ian , Rohatgi Anand , Gill Jason , Leinhard Olof , Sattar Naveed
Published: November 2024

Background:
South Asians (SAs) have higher risk of diabetes and cardiovascular disease compared with other ethnicities; however, detailed analyses of their body composition profile (BCP), including ectopic fat, muscle mass and muscle quality are lacking. Such data may help explain the higher rate of type 2 diabetes (T2D) in SAs, as muscle mass and quality are increasingly recognized as being linked to long-term health outcomes.

Aims:
This study utilizes imaging data from the UK Biobank cohort to compare body composition between SAs and white Europeans (EUR) to better understand ethnic differences in fat distribution and muscle composition.

Hypothesis:
We predict that SAs will have higher levels of ectopic fat (visceral-, liver-, and muscle fat) than matched EUR, which may explain their higher rates of T2D.

Methods:
Using UK Biobank imaging data captured by MRI, we compared body composition data in SAs (n=323) without T2D relative to age, sex, height and weight-matched EUR (matched 5:1 to SA group). We also compared BCP in 66 SAs with T2D versus matched EUR (matched 3:1 to SA group).

Results:
SAs without T2D had higher overall levels of body fat compared to EUR (mean difference in: visceral adipose tissue 0.20 L; abdominal subcutaneous adipose tissue 0.93 L; liver fat 0.92 percentage points (pp); muscle fat infiltration (MFI) 0.59 pp, all p</=0.001) and lower muscle volume (mean difference -0.61 L, p<0.001) (p-values adjusted for sex, age, and BMI). Adverse muscle composition (MFI >75
th
percentile and muscle volume <25
th
percentile) was more prevalent in SAs (19.9% vs 7.9%, p<0.001). Differences remained significant after further adjustment for prevalent disease, lifestyle and socioeconomic factors. SAs with T2D had similar BCP compared with matched EUR with T2D.

Conclusions:
SAs without T2D have greater visceral, liver, and muscle fat accumulation, and lower muscle volume compared to EUR. These findings may underlie their greater risk for T2D and atherothrombotic outcomes, especially as BCP was similar when comparing SAs with T2D to matched EUR with T2D. Lifestyle modification to increase physical activity and reduce weight gain may offset cardiometabolic risks in SAs through favorable changes in body composition.
Abstract 4143921: Adaptation of Prompt-enabled Segment-Anything-Model Enhance the Accuracy and Generalizability of Cine Cardiac Magnetic Resonance Segmentation
Authors: Chen Zhennong , KIM SEKEUN , Ren Hui , Kim Sunghwan , Yoon Siyeop , Li Quanzheng , Li Xiang
Published: November 2024

Introduction:
Accurate segmentation of cine cardiac magnetic resonance (CMR) throughout the cardiac cycle is essential for comprehensive cardiac functional analysis. However, current deep-learning (DL) approaches often suffer from reduced accuracy on unseen datasets due to generalizability issues. The Segment-Anything Model (SAM) is a new prompt-enabled segmentation foundation model trained on one billion natural images, known for its generalizability and user-defined prompts.

Hypothesis:
Adapting SAM for cine CMR segmentation can improve accuracy and generalizability on previously unseen CMR data.

Methods:
We adapted SAM for cine CMR segmentation by incorporating a temporal attention mechanism to maintain temporal consistency across the cardiac cycle and parameter-efficient transfer learning to segment the left ventricle (LV) and myocardium (MYO). User-defined bounding box prompts were used around MYO at end-diastole and end-systole phases to guide the segmentation region. The model can output segmentations for all phases throughout one cardiac cycle at once. We evaluated the model using a multi-center, multi-vendor (M&M) international dataset of 136 cine CMR cases, which was unseen during model training.The trained model was applied to this dataset without fine-tuning to assess generalizability. We compared SAM with three state-of-the-art (SOTA) cine CMR DL segmenters. Segmentation accuracy was evaluated using the Dice coefficient. Clinical parameters, including LV end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF), were compared between manual and automatic measurements.

Results:
The adapted SAM with box prompts demonstrated superior generalization compared to SOTA methods (p<0.01 by one-sided Wilcoxon test). The Dice coefficient was 0.937±0.024 for LV and 0.870±0.029 for MYO, with no significant differences across different centers and vendors, except for one center. The agreement for LVEDV and EF was high, with r = 0.995 and bias = 4.21±6.75 ml for LVEDV and r = 0.97 and bias = -0.50±3.75% for EF. Using bounding box prompts around the MYO region enhanced its segmentation accuracy from 0.853±0.032 to 0.870±0.029 (p<0.05) compared to no prompts.

Conclusion:
Adapting SAM with box prompts enhances accuracy and generalizability in cine CMR segmentation..
Abstract 4143943: Minimally-Invasive Intrapericardial Injections under Direct Visualization via Thoracic Cavity Access in Infant and Pediatric-sized Swine
Authors: O'Hara Ryan , Kumthekar Rohan , Opfermann Justin , Gonzalez Bryan , Clark Bradley , Berul Charles
Published: November 2024

Background:
Intrapericardial delivery of antiarrhythmic drugs and regenerative therapies is a growing field for infants and children who suffer from certain cardiac diseases. Typically, this is performed under fluoroscopic and/or ultrasonic guidance. Pericardial access via thoracoscopy provides direct visualization of the heart, enabling the operator to avoid injuries to critical cardiac structures, and to visualize intrapericardial injections for targeted drug therapies.

Objective:
To demonstrate the feasibility of minimally-invasive intrapericardial injections under direct visualization using a novel thoracic access port in immature swine.

Methods:
Minimally-invasive procedures were performed in 12 Sinclair piglets (8 at 1-month old, 4.1 ± 1.5 kg; 4 at 5-months old, 26.3 ± 1.0 kg). A single 1.2 cm incision just to the left of the subxiphoid process allowed for temporary insertion of the thoracic access port. An EndoCAMeleon thoracoscope with active insufflation was used to visualize the thoracic cavity and the heart (pericardium). An 18-gauge needle was used to gain access to the intrapericardial space. Saline or dyed saline was injected through the needle and/or sheath with direct visualization and confirmed on the thoracoscope. Following the procedure, the access tool was removed and the incision was sutured closed. All studies were performed under IACUC approval.

Results:
Minimally-invasive intrapericardial injections were successfully performed in 8 infant- and 4 child-sized swine with real-time visualization (Figure). The average time between the incision and pericardial needle access was 16.8 ± 5.0 minutes. No adverse events were observed from either the intrapericardial fluid injection or the use of the thoracic access tool.

Conclusion:
We demonstrated the feasibility and safety of minimally-invasive intrapericardial injections under direct visualization in swine using a novel thoracic access port. Direct targeted pericardial injection of medications or gene therapies can be performed using this technique. This approach holds promise for providing an alternative to cardiac restoration in infant and pediatric patients who are not amenable to traditional therapies.
Abstract 4143957: Assessing blood-nerve barrier permeability to nanoparticles over the course of experimental autoimmune neuritis
Authors: Kaur Chanpreet , Cabe Maleen , Langert Kelly
Published: November 2024

The acute inflammatory demyelinating polyneuropathy (AIDP) subtype of Guillain–Barré syndrome (GBS) is a debilitating autoimmune peripheral neuropathy. Treatment options are limited to nonspecific immunomodulation and are often ineffective. Systemic or local delivery of several candidate therapeutics have been demonstrated to attenuate the severity of experimental autoimmune neuritis (EAN), an established rat model of AIDP. However, advancement of these findings has been limited due to high doses or impractical routes of administration that are not clinically translatable. While the blood nerve barrier (BNB) normally restricts access of circulating molecules to the endoneurium, during the acute inflammation associated with some peripheral neuropathies, including AIDP, the BNB exhibits increased vascular permeability and enables immune cell infiltration. These pathological changes contribute to disease, but they may also offer a unique opportunity to access the otherwise restricted peripheral nerve microenvironment for therapeutic delivery. In other fields, it is established that circulating particles with favorable size and morphology will passively accumulate in sites with fenestrated vasculature through an enhanced permeation and retention process. In this work, we tested the hypothesis that nanoparticles (NPs) with surfaces modified for prolonged circulation will accumulate in affected nerves in rats with EAN through a similar process. We assessed BNB permeability to intravenously administered small molecules (Evan’s Blue Dye) and spectrally defined NPs (58 and 134 nm polystyrene) over the length of the nerve and the course of EAN. NPs were obtained as commercially available, carboxylated Fluospheres to which we covalently attached poly(ethylene) glycol (PEG) amine using carbodiimide coupling. We also quantified immune cells present in nerve cross sections and compared our findings to naïve rats to determine the correlation between immune cell infiltration, BNB permeability, and NP accumulation. Results demonstrate increased BNB permeability to small molecules at disease onset and permeability to NPs up to 138 nm in size during the intermediate to peak stages of the disease. NP permeability coincides with CD68+ macrophage infiltration.
Abstract 4143958: NADPH oxidase-4 is an early driver of cardiac myofibroblast differentiation and cellular senescence in dilated cardiomyopathy
Authors: Berhanu Samuel , Antolic Andrew , Shin Yoon , kato kosuke , Kleinhenz Jennifer , Jiao Zhe , Hecker Louise , Burke Michael
Published: November 2024

Background:
Myofibroblasts mediate tissue fibrosis and are a driver of disease progression in heart failure (HF). Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) are required for transforming growth factor-beta (TGFb)-induced myofibroblast activation. Therapeutic targeting of NOX4 inhibited fibrosis development and reversed existing fibrosis in an aging model of lung fibrosis. However, the cell-specific roles of NOX4 in the heart have not been fully explored.

Objective:
We sought to define the cardiac cell-type specific expression and role of NOX4 activation in the progression to HF.

Methods:
Mice carrying a mutation in the phospholamban gene (PLNR9C) develop progressive dilated cardiomyopathy (DCM), fibrosis and HF. Cardiac cells were isolated using the Langendorff hanging heart method followed by flow cytometry. Single nucleus RNA-sequencing (snRNA-seq) was performed to define cell-specific gene expression. Immortalized mouse cardiac fibroblasts were treated with TGFb to establish longitudinal gene expression patterns with differentiation to myofibroblasts.

Results:
Nox4 was upregulated in hearts (mRNA 8.5-fold; protein 3.1-fold; n=4, p<0.01) and isolated cardiac fibroblasts (mRNA 6.1-fold; protein 2.5-fold; n=3, p<0.01) from PLNR9C mice with HF but not age-matched wild type (WT) mice or young PLNR9C mice prior to the onset of DCM. Using snRNA-seq, we identified fibroblasts as the primary cell type expressing Nox4 in the heart in WT and PLNR9C mice; notably there was almost no expression of Nox4 in cardiomyocytes. This was consistent with published data in mouse heart analyzed from the NCBI GEO database. Fibroblasts from PLNR9C hearts with DCM had elevated ROS levels (Amplex Red assay 2.5-fold, p<0.01, n=3) and displayed a senescent phenotype, with elevated levels of the senescence markers p16 (2.1-fold, p<0.01, n=3) and b-galactosidase (1.7-fold, p<0.01, n=3), compared to fibroblasts from age-matched WT mice. In immortalized cardiac fibroblasts activated with TGFb, Nox4 increased 12 hours prior to expression of myofibroblast-specific genes (Postn, Col3a1). Co-treatment with siRNA targeting SMAD3 or the bromodomain and extraterminal (BET) inhibitor JQ1 blocked TGFb-induced Nox4 expression and fibroblast to myofibroblast differentiation.

Conclusions:
These data identify NOX4 as a putative proximal mediator of cardiac fibroblast activation in mice with genetic DCM and suggest that cardiac fibroblasts develop a premature aging phenotype in HF.
Abstract 4143977: Cardiovascular Toxicities in Chimeric Antigen Receptor Therapy in Relapsed and Refractory Multiple Myeloma and Lymphoma using FAERS database.
Authors: Ayoobkhan Fathima Shehnaz , Parvataneni Tarun , Balasubramanian Suryakumar , Ganiyani Mohammad Arfat , Reddy Matta Temujin
Published: November 2024

Introduction:
Chimeric Antigen Receptor T-cell therapy (CAR-T) has revolutionized the treatment of relapsed refractory multiple myeloma (RRMM) and lymphoma over the past decade. Our objective is to examine the incidence, patterns, and outcomes of cardiac events in patients with RRMM and lymphoma who are receiving CAR-T therapy, utilizing the FDA Adverse Event Reporting System (FAERS) database.

Methods:
We employed the FDA Adverse Event Reporting System (FAERS) database and the Medical Dictionary for Regulatory Activities (MEDRA) to conduct a retrospective post-marketing pharmacovigilance inquiry. We analyzed the incidence of cardiac events associated with six CAR-T products, namely Idecabtagene vicleucel, Cilitacabtagene autoleucel, Axicabtagene ciloleucel, Tisagenlecleucel, Lisocabtagene maraleucel, and Brexucabtagene autoleucel, since their FDA approval (accessed 05/01/2024). We assessed the cardiotoxicities such as coronary artery disease (CAD), myocardial infarction (MI), arrhythmia, heart failure, and hypotension.

Results:
A total of 12,949 adverse events, including Axicabtagene ciloleucel (n=6222, 48%), Brexucabtagene autoleucel (n=1127, 8.7%), Tisagenlecleucel (n=3290, 25.4%), Lisocabtagene maraleucel (n=463, 3.5%), Idecabtagene vicleucel (n=722, 5.5%), and Cilitacabtagene autoleucel (n=1125, 8.6%). Of those, 675 cases (5.2% of the total) that were related to cardiac events, regardless of their severity. The cardiotoxicity incidence was highest in Brexucabtagene autoleucel (n=85,7.5%), followed by Idecabtagene vicleucel (n=50,6.9%), Tisagenlecleucel (n=208,6.3%), Axicabtagene ciloleucel (n=278,4.5%), Lisocabtagene maraleucel (n=17,3.6%), and Ciltacabtagene autoleucel (n=37,3.2%).

Cytokine release syndrome (CRS) is linked to nearly 440 cardiac events,accounting for 65% of all cardiac events.

The most prevalent cardiotoxic event was Atrial Fibrillation (122), followed by the development of heart failure (113), Ventricular arrhythmia (108), hypotension (87), and Brady arrhythmia (41).

The recipients of Brexucabtagene autoleucel had the highest mortality rate (n = 26,2.3%), followed by those receiving Tisagenlecleucel (n = 71,2.1%) and Lisocabtagene maraleucel (n = 10,2.1%).

Conclusion:
The cardiotoxic properties of CAR-T therapy can lead to fatal adverse events. Improving outcomes and preventing mortality in these populations can be achieved through timely monitoring.
Abstract 4143979: Incidence of Right Ventricular Dysfunction in an Echocardiographic Referral Cohort
Authors: Garry Jonah , Huang Shi , Annis Jeffrey , Kundu Suman , Hemnes Anna , Freiberg Matthew , Brittain Evan
Published: November 2024

Introduction:
RV dysfunction (RVD) is one of the few cardiovascular conditions with unknown incidence rate (IR). We examined the rates, risk factors, and HF hospitalization hazard associated with incident RVD in pts referred for TTE.

Methods:
We extracted tricuspid regurgitant velocity (TRV) and TAPSE from all TTEs at Vanderbilt between 2010-2023. We selected the first TTE with normal RV function (TAPSE =/> 17mm) and a reported TRV. The primary outcome was new RVD (TAPSE < 17mm) and secondary outcome was time to HF hospitalization after second TTE. We used Poisson regression and multivariable cox models to estimate IRs and hazard ratios, adjusted for demographics, comorbidities, and TTE measures. We estimated a minimum IR in all pts with a baseline echo (Full Cohort) and a maximum IR among pts with a repeat TTE (Repeat TTE Cohort).

Results:
We identified 45,753 pts (63 years [IQR 50-72], 45% Male, 13% Black) with normal RV function at baseline, of whom 13,735 pts (30%) underwent a repeat TTE and 4,198 pts (10%) developed RVD. The IR of RVD in the Full Cohort was 3.2/100 person-yrs (95%CI 3.1-3.3) and 8.2 (95%CI 8.0-8.5) in the Repeat TTE Cohort. IRs were higher in pts with pulmonary hypertension vs without and increased with higher RVSP (
Figure 1)
. Risk factors for incident RVD included HF (HR 1.88; 95%CI 1.75–2.03), AF (HR 1.54; 95%CI 1.44–1.65), and left-sided valvular disease (HR 1.68; 95%CI 1.53–1.85). Baseline RVSP was associated with TAPSE decline beginning near 35mmg (
Figure 2A
). Incident RVD was associated with increased hazard of HF hospitalization (HR 2.02; 95% CI 1.85-2.21). Hazard of HF hospitalization increased when TAPSE declined 5mm or greater (
Figure 2B
).

Conclusions:
RVD incidence is substantial among patients referred for TTE and warrants close monitoring when RVSP >35mmHg. Incident RVD and change in TAPSE >5mm were associated with increased hazard of HF hospitalization, even after adjustment for prevalent HF.
Abstract 4143993: SEX DISPARITIES IN HUMAN CALCIFIC AORTIC VALVE STENOSIS ASSESSED BY DISEASE STAGE-SPECIFIC HISTOPATHOLOGICAL AND PROTEOMIC ANALYSES
Authors: Clift Cassandra , Blaser Mark , Schlotter Florian , Robson Simon , Body Simon , MUEHLSCHLEGEL JOCHEN , Aikawa Masanori , Singh Sasha , Aikawa Elena
Published: November 2024

BACKGROUND:
Calcific aortic valve stenosis (CAVS) is a global clinical burden, impacting around 2% of the population over 65 years of age. No pharmacotherapeutics exist, with surgical repair and transcatheter valve replacement being the only intervention. Females are underrepresented in studies of CAVS, leading to delay in timely intervention and increased mortality. Histopathology demonstrates female CAVS presents with decreased valvular calcification but increased fibrosis and severity of symptoms. We hypothesize that the underlying molecular mechanisms contributing to disease progression and fibrocalcific burden in AS differs between male and female patients. Our goal for this study is to use previously acquired proteomic datasets of a clinically-defined human AS cohort to examine sex disparities and underlying sex-specific disease signatures.

METHODS and RESULTS:
Age-matched human AS tissue samples (n=4 females, n=14 males) were each segmented into non-diseased, fibrotic, and calcified disease stages and analyzed using LC-MS/MS proteomics and quantitative histopathology. Unbiased principal component analysis shows sex- and stage-specific proteome clustering. AS pathogenesis drove sex-specific disparities in the valvular proteome: 338/1503 total proteins were differentially-enriched by sex across disease stages. Compared to sex-specific non-diseased controls, female fibrotic tissue resulted in 2.05-fold greater number of differentially-enriched proteins than did male fibrotic tissue (female: 113, male: 55; q<0.05 threshold). In contrast, female calcific tissue identified 2.03-fold less differentially-enriched proteins than male calcific tissue (female: 255, male 519; q<0.05 threshold). By Gene Ontology enrichment (odds ratio ranked, q<0.05), proteins enriched in male fibrotic AS segments preferentially associate with superoxide regulation, sterol transport, and endocytosis while extracellular matrix (ECM) organization and endothelial cell migration were hallmarks of female-specific AS fibrosis. Remarkably, immune and complement response were ubiquitous drivers of calcification, female segments were uniquely enriched in ECM processes.

CONCLUSIONS:
We reveal a sexually-dimorphic AS proteome, including the novel overabundance of ECM remodeling pathways in female calcified aortic valve tissues. This analysis allows for identification of potential sex-specific protein drug targets implicated in AS pathobiology.
Abstract 4144000: The association between statins and immune checkpoint inhibitor-associated cardiotoxicity
Authors: Chi Kuan Yu , Song Junmin , CHIANG CHO HUNG , Chang Yu-Cheng , yuanping HSIA , Chang Yu , Chiang Cho Han
Published: November 2024

Background:
Immune checkpoint inhibitors (ICIs) have been associated with major adverse cardiovascular events (MACE) that carry high morbidity and mortality. Statins are widely used for the primary prevention of MACE in patients with a high risk of atherosclerotic cardiovascular disease. However, the impact of statins on MACE associated with ICIs remained unclear.

Research Question

Is stain use associated with a reduction in MACE in patients treated with ICI?

Aim

To assess the effectiveness of statins on the primary prevention of MACE in patients treated with ICI.

Methods:
We conducted a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network database. We included all adult cancer patients who were treated with an ICI between March 2011 and March 2023. We excluded patients with a history of MACE, defined as a composite of myocardial infarction, myocarditis, pericarditis, and cardiovascular death. Patients who received statins prior to ICI initiation were compared to those who did not receive statins prior to the start of ICI therapy. The primary efficacy outcome was MACE. Secondary efficacy outcomes were indivicual MACE. The safety outcomes included all-cause mortality and adverse events associated with statins. Cox proportional hazard ratios (HR) were

calculated to compare study endpoints occurring within 1 year of ICI initiation between statins users and non-users.

Results:
Of 73,988 patients eligible for inclusion, 12,653 patients who received statins were matched to those who did not receive statins. The most common indication for an ICI was lung cancer (41%) and the most commonly administered ICI was pembrolizumab (50%). In a Cox proportional hazards analysis, patients on a statin were associated with a lower risk of MACE (HR, 0.83; 95% CI, 0.72-0.94) as compared to patients not on a statin. There was a reduction in the risk of myocardial infarction, cardiovascular death, and a lower trend of myocarditis among patients who received statins. Patients on a statin had a lower rate of all-cause mortality without an increase in adverse events.

Conclusions:
Statins were associated with a reduction in MACE and all-cause mortality among cancer patients receiving ICI therapy.
Abstract 4144007: Regional differences of treatment disparities in Black and White patients with peripheral artery disease across the United States
Authors: Vogel Birgit , Dangas Katerina , Di Muro Francesca , Sartori Samantha , OLIVA ANGELO , Dangas George , Krishnan Prakash , Yoon Harrison , Etter Katherine , Erim Daniel , Pylypchuk Yuriy , Keever Rachel , Mehran Roxana
Published: November 2024

Background:
Racial disparities exist regarding treatment and outcomes of peripheral artery disease (PAD) in the United States (US). Black versus White Americans are more likely to have delayed PAD diagnosis and are at higher risk of lower limb amputation.

Aim:
To investigate regional differences in PAD treatment disparities between Black and White Americans.

Methods:
Data on 2,376,300 Black and White Medicare Fee-For-Service beneficiaries with a first diagnosis of PAD between 2018 and 2022 were studied. Patient counts for diagnosis, revascularization, and amputation were summarized for each state and used to create forest plots of revascularization and amputation rates. County-level rates of revascularization and amputation rates by race were also correlated against publicly available county-level Social Vulnerability Index (SVI).

Results:
Black versus White patients were slightly younger (75.8±7.9 years vs 76.9±7.8 years; p<0.001) and more likely female (54.7% vs 47.8%; p<0.001) with higher prevalence of comorbidities. Black patients were more likely to undergo procedures for PAD compared with White patients with marked variation between states (Figure 1). Black patients were also more likely to have revascularizations or amputations compared with White patients (8.4% vs 7.0%; p<0.001 and 3.0% vs 0.9%; p<0.001, respectively). Correlations between county-level SVI and revascularization rates were stronger among white patients (rho = 0.08, p-value = 0.005) compared to Black patients (rho = 0.04, p-value = 0.40). Similarly, correlations between county-level SVI and amputation rates were stronger among White patients (rho = 0.27, p-value <0.01) compared to Black patients (rho = 0.12, p-value = 0.17).

Conclusion:
Treatment disparities between Black and White patients with PAD differed markedly in the US by state with largest racial differences in amputation rates occurring among Southern states. Community-level risk, as identified by the SVI, may play a role in certain treatment patterns and warrant further investigation. Full data on this will be presented.
Abstract 4144027: AI-enabled multimodal risk stratification of probable transthyretin amyloid cardiomyopathy from point-of-care electrocardiography and ultrasound: A report from the TRACE-AI Study
Authors: Oikonomou Evangelos , Sangha Veer , Dhingra Lovedeep , Aminorroaya Arya , Pedroso Camargos Aline , Coppi Andreas , Miller Edward , Gallegos Cesia , Khera Rohan
Published: November 2024

Introduction:
Artificial intelligence (AI) tools may enable the detection of transthyretin amyloid cardiomyopathy (ATTR-CM) from 12-lead electrocardiographic (ECG) images and point-of-care ultrasonography (POCUS). The TRACE-AI study is designed to examine the burden and outcomes of potentially undiagnosed cases through the opportunistic deployment of multimodality AI algorithms.

Research Question:
To explore the burden and prognosis of probable ATTR-CM identified by opportunistically deployed AI-ECG and AI-POCUS in the emergency department (ED).

Methods:
Across a diverse, 5-hospital health system, we identified individuals never diagnosed with ATTR-CM who had previously sought care in the ED during 2013-2023 and had no history of heart failure (HF) at baseline. Among these, 17,564 individuals (median age 52 [IQR: 36-66] years; 9,407 [53.6%] women, 4,520 [25.7%] Black and 3,180 [18.1%] Hispanic) had undergone a 12-lead ECG and POCUS within one day of each other (
Fig. 1
). We deployed validated AI algorithms for ATTR-CM from 12-lead ECG images and POCUS videos to obtain study-level probabilities of ATTR-CM. We stratified the population based on validated AI-ECG and AI-POCUS thresholds and examined the associations of screen positivity with mortality and HF hospitalization in Cox models adjusted for age, sex, hypertension, and diabetes mellitus.

Results:
Among 17,564 eligible individuals, 780 (4.4%) screened positive by AI-ECG, and 286 (1.6%) by both modalities. Over a median follow-up of 2.2 [IQR: 1.2-5.9] years, there were 1,226 deaths and 458 HF hospitalizations. Screen positivity on both modalities conferred a 1.7-fold higher adjusted risk of death (adj. HR 1.70 [95%CI: 1.31-2.22],
Fig. 2A
) and 2.2-fold higher risk of HF hospitalization (adj. HR 2.18 [95%CI: 1.44-3.30],
Fig. 2B
), compared with those screening negative on both modalities. Even among those screening positive on one modality, there was a significant 1.2-fold and 1.5-fold higher risk of death and HF hospitalization relative to the reference group (
Fig 2A-B
).

Conclusions:
Scalable AI technology applied to ECG images and POCUS as part of their ED care identified that ~1.6% of individuals screened positive for ATTR-CM on both modalities but without eventual clinical diagnosis. This group of patients with probable undiagnosed ATTR-CM had a higher risk of long-term adverse outcomes. This underscores the need for improving ATTR-CM diagnostic rates through scalable technology applied in routine care.
Abstract 4144031: Colchicine for prevention of pericarditis after catheter ablation: A systematic review and meta-analysis.
Authors: Mashaly Doaa , Hassan Ayman , Mustafa Qafesha Ruaa , Elbadry Menna , Dervis Muhi , Mohamed Ahmed , Abdelaziz Ahmed , Ramadan Shrouk , Abdelazeem Basel , LAVIE Carl , Slipczuk Leandro
Published: November 2024

Introduction:
Catheter ablation (CA) therapy is well established therapy for different types of atrial fibrillation, with some concern including post ablation pericarditis which increases the morbidity and mortality. Colchicine, known for its anti-inflammatory effects has shown to be effective in reducing the incidence of perioperative AF after cardiac surgery. However, the efficacy of post ablation colchicine is still debatable. We aimed to establish evidence on the use of colchicine for preventing pericarditis after catheter ablation.

Methods:
We searched PubMed, Scopus, WOS and Cochrane until May 2024 for relevant studies that assessed colchicine after CA. The primary outcome of interest was the incidence of pericarditis following AF. Other secondary outcomes were the incidence of pericardial effusion, GI adverse events, and hospitalization rates.

Results:
A total of nine studies were included with a total of 2795 patients aged 66 to 69.4 years, Colchicine administration before catheter ablation showed a significant decrease in the occurrence of clinical pericarditis after AF ablation compared to placebo (RR=0.38; 95% CI: 0.27, 0.53). Moreover, colchicine was favored to decrease the incidence of AF recurrence rate at 3, 6, and 12 months with the following values, respectively (RR=0.58, 95% CI: 0.42 to 0.80, 0.69, 95% CI: 0.5 to 0.97, and 0.76, 95% CI: 0.66 to 0.87). On the other hand, colchicine was associated with a significant increase in GI adverse events (RR= 2.62, 95% CI: 1.57, 4.37).

Conclusion:
Colchicine was found to be a promising intervention for reducing the incidence of pericarditis following atrial fibrillation ablation. Despite some contradictory data about gastrointestinal side effects, cautious dosage measures, such as weight-adjusted doses, may improve tolerability while maintaining efficacy in reducing post-ablation events.