bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4139928: Ketone Body Metabolism Exerts an Anti-hypertrophic Effect on Cardiomyocytes by Alleviating Fatty Acid Overload and Increasing Glucose Utilization.
Authors: Yamada Toshihiro , morikawa kei , Fujiyama Akira , Nagakura Takumi , Yuquing Xu , Kataoka Miho , Kikuchi Kenta , Kurotaki Daisuke , Umemoto Terumasa , Hino Shinji , Bundo Miki , Iwamoto Kazuya , Ahmed Zeeshan , Linna-Kuosmanen Suvi , Hanatani Shinsuke , Usuku Hiroki , Matsuzawa Yasushi , Izumiya Yasuhiro , Yamamoto Eiichiro , Tsujita Kenichi , Arima Yuichiro
Published: November 2024

Background:
Ketone body metabolism, known for its multifaceted effects, is gaining attention as a potential therapeutic target for cardiovascular diseases. However, the impact of ketone bodies on cardiac hypertrophy and Heart Failure with Preserved Ejection Fraction (HFpEF) remains unclear.

Research Questions:
To elucidate the effects of ketone bodies on cardiac hypertrophy.

The aim of the present research is to investigate the impact of ketone bodies on cardiac hypertrophy induced by metabolic abnormalities using organ-specific ketone body synthesis-deficient mice.

Methods:
Obesity and hypertension were induced by a high-fat diet combined with NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME) (Combined Stress), and the resultant cardiac hypertrophy and ketone body synthesis were evaluated. Subsequently, organ-specific knockout mice of HMG-CoA synthase 2 (
Hmgcs2
), a rate-limiting enzyme in ketone body synthesis, were subjected to Combined Stress to assess the impact on cardiac hypertrophy. To conduct a metabolism-focused analysis, cell type-specific nuclei were isolated and subjected to RNA sequencing (RNA-seq) and comprehensive metabolomics analysis. To evaluate the direct effects of ketone bodies, H9C2 cells, rat cardiac cells ,were treated with β-hydroxybutyrate, followed by analysis of oxygen consumption and metabolomics.

Results:
Combined Stress resulted in increased myocardial cross-sectional area and enhanced ketone body synthesis in the liver and heart. Hepatocyte-specific Hmgcs2 knockout mice (

Hmgcs2
ΔHep

) subjected to Combined Stress exhibited exacerbated myocardial hypertrophy (cardiomyocyte cell size;

Hmgcs2
flox

: 322.8 ± 88.3 μm
2
:

Hmgcs2
ΔHep

: 444.0 ± 118.5 μm
2
; p < 0.0001). RNA-seq analysis revealed that the upregulation of glycolytic genes induced by Combined Stress did not occur in

Hmgcs2
ΔHep

mice, and a metabolic phenotype favoring fatty acid oxidation persisted. In the liver, hepatocyte destruction and increased serum fatty acid levels were observed. Additionally, H9C2 cells treated with β-hydroxybutyrate showed decreased fatty acid utilization and increased glucose utilization.

Conclusion:
In cardiac hypertrophy induced by obesity and hypertension, ketone body synthesis mitigates fatty acid overload and promotes glucose utilization, thereby exerting an anti-hypertrophic effect.
Abstract 4139929: The mechanisms of Mid-ventricular obstruction in patients with hypertrophic cardiomyopathy: Insight from an echocardiographic study
Authors: Lu Zhengyang , meng yanhai , Nie Changrong , Wang Shuiyun
Published: November 2024

Background:
Mid-ventricular obstruction (MVO) is a rare subtype of hypertrophic cardiomyopathy (HCM) , but it is associated with severe symptoms and worse clinical outcomes. Whereas the mechanisms of MVO has not fully elucidated. Therefore, we sought to investigate the mechanisms of MVO via an echocardiographic analysis.

Method:
We retrospectively enrolled 239 patients diagnosed with HCM in this study. All patients were divided into non-obstructive HCM group (N=51), isolated left ventricular outflow (LVOT) obstructive HCM (oHCM) group (N=130), and MVO group (N=58) based on the initial echocardiographic evaluation.

Result:
Compared to patients with oHCM, patients with MVO were much younger (43.48±11.45 vs. 49.25±12.10, p <0.05), less likely to be female (54 (41.5%) vs 12 (20.7%), p <0.05), had a lower left atrial diameter (41.64±5.82 vs. 43.99±6.30, p <0.05), a higher mid-septal thickness (21.40±4.24 vs. 18.88±3.30, p <0.05), a lower mean global longitudinal strain (-10.59±4.31 vs. -14.41±3.83, p <0.05), a longer anterior papillary muscles (APM) length ( 48.91±7.37 vs. 41.13±6.93, p< 0.05), a shorter distance between APM and septum (APM-IVS) ( 11.19±2.53 vs. 17.97±3.45, p<0.05), a higher prevalence of mid-septal bundle (56 (96.6%) vs. 74 (56.9%), p <0.05). Multinomial logistic analysis indicated that compared to patients with non-obstruction HCM patients, BMI (Odd ratio [OR] 1.321, 95% confidential interval [CI] 1.116-1.564, p< 0.001) , APM-IVS (OR 0.404, 95%CI 0.316-0.517, p< 0.001), APM length (OR 1.147, 95% CI 1.051-1.251, p= 0.002), and mid-septal thickness (OR 1.202, 95% CI 1.01-1.43, p= 0.038) were independent risk factors of MVO. Furthermore, compared to patients with oHCM, APM-IVS (OR 0.430, 95%CI 0.341-0.542, p<0.001), the presence of mid-septal bundle (OR 8.376, 95%CI 1.513-46.365, p=0.015), and APM length (OR 1.081, 95%CI 1.011-1.157, p = 0.023) were significantly associated with MVO.

Conclusion:
APM-IVS, APM length and mid-septal thickness played vital roles in the development of mid-obstruction in hypertrophic cardiomyopathy, which may offer a clue for surgical strategy.
Abstract 4139937: Plant-Based Diet and All-Cause and Cause-Specific Mortality among Patients with Cardiovascular Disease: A Population-Based Cohort Study
Authors: Liu Xiaohui , Wan Xuzhi , Zhuang Pan , Zhang Yu , Jiao Jingjing
Published: November 2024

Background:
The role of plant-based diet in preventing premature death among patients with cardiovascular disease (CVD) remained unknown. To explore the relationship of plant-based dietary patterns with all-cause and cause-specific mortality among patients with CVD.

Methods:
A sum of 10,841 participants with CVD at baseline were followed up in the UK Biobank. We constructed three types of plant-based diet indexes [an overall plant-based diet index (PDI), a healthy PDI (hPDI), and an unhealthy PDI (uPDI)] by assigning different weights to various food groups from web-based 24-h dietary recall questionnaires. The national death registry documented primary causes of death. The Cox proportional hazards regression models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality.

Results:
Over a median of 11.3-year follow-up, 1,275 death cases were ascertained. After multivariable adjustment, PDI had a negative correlation with all-cause mortality [HR
T3vsT1
: 0.81 (0.70-0.94), P
trend
=0.005] and CVD mortality [HR
T3vsT1
: 0.78 (0.61-0.99), P
trend
=0.040], while uPDI displayed a positive correlation with all-cause mortality [HR
T3vsT1
: 1.33 (1.16-1.53), P
trend
<0.001] and CVD and cancer mortality. Additionally, in mediation analyses, serum concentration of C-reactive protein (CRP) accounted for 6.2%, 4.0%, and 5.1% of the relationship between uPDI and all-cause, CVD, and cancer mortality, respectively. No significant associations were detected between hPDI and mortality.

Conclusions:
Among patients with CVD, stronger adherence to PDI correlated with reduced all-cause and CVD mortality rates. Conversely, adherence to uPDI showed an association with increased mortality, possibly attributable to elevated levels of circulating CRP. Our findings support dietary guidelines that recommend limiting the consumption of unhealthy plant-based foods.
Abstract 4139938: Lipidomic signature of acute ischemic and hemorrhagic stroke
Authors: Stamenkovic Aleksandra , Chong Michael , Aliani Michel , Pierce Grant , Pare Guillaume , Aukema Harold , Ravandi Amir
Published: November 2024

Introduction:
Stroke is the second leading cause of death worldwide and the leading cause of disability. Without a plasma biomarker care is often delayed. The brain is rich in lipids, which readily cross the blood-brain barrier, and therefore represent a target for biomarkers of stroke. The study aimed to determine the lipidomic changes in plasma in stroke patients through an untargeted and targeted analysis.

Methods:
A cohort of 482 patients from the INTERSTROKE study was included in the analysis. This included 241 stroke patients (120 ISCH, 121 HEM) and 241 age and sex-matched controls. A LC/MS/MS platform was used to perform a detailed lipidomic and oxylipidomic analysis of plasma. Biomarker analysis was performed using the Random Forest Classification algorithm (RFC).

Results:
Lipidomic analysis identified 141 lipid species and 32 oxylipins significantly altered in ISCH stroke compared to control and 167 lipid species and 34 oxylipins in HEM stroke. Between ISCH and HEM stroke there were in 87 significant lipids. There was a 141 % increase in phosphatidylserine (PS) 40:6 (p< 0.0001) in patients with HEM stroke compared to ISCH, whereas prostaglandin E2 was found to be 94% higher (p<0.0001) in ISCH stroke. RFC model identified lysophosphatidylcholine (LPC) 14:0 and 15-oxoETE as the most important features contributing to classification between control and stroke with a mean AUC score of 0.81 and 0.69 respectively. PS 40:6 and 14-HDoHE are the most important features contributing to separating ISCH and HEM stroke, with mean AUC scores of 0.84 and 0.67, respectively. PC 34:1 and PC-O 36:3 were found to be the biggest predictors of stroke outcomes at 30 days, measured by The Modified Rankin Score (mRS) score. In addition, four lipids: Ceramide 24:1, C14 Tetradecanoyl Carnitine, trihexosylceramide 16:0, and PS 40:6 were found to be the independent predictors of mortality in patients with stroke.

Conclusion:
We have demonstrated significant alterations in the human plasma lipidome during acute stroke, revealing distinct differences between HEM and ISCH subtypes. These lipid profiles not only differentiate between stroke subtypes but also predict clinical outcomes. Given the current lack of plasma biomarkers for stroke, our study underscores the potential of lipid molecules as valuable biomarkers for stroke diagnosis and prognosis.
Abstract 4139940: Safety and Efficacy of Self-Expanding vs Balloon-Expandable Valves for Transcatheter Aortic Valve Replacement in Patients with Aortic Stenosis: A Systematic Review and Real-World Meta-Analysis
Authors: Siddiqui Abdul Hannan , Mansoor Javeria , Habib Hashir , Devi Priya , Waheed Mariyam , Hotwani Priya , Saleem Kashaf , Kumar Mukesh , Kumar Laksh , Hussain Syed Anas , Hassan Ahmed Bin , Moeed Abdul , Najeeb Hala , alam mahboob
Published: November 2024

Background:
There are two approved methods for transcatheter aortic valve replacement (TAVR) namely balloon-expandable valves (BEV) and self-expanding valves (SEV). While several randomized controlled trials (RCTs) have compared the efficacy of SEV and BEV, the generalizability of their findings is questioned. Therefore, to generate concrete evidence regarding the superiority between the two, we conducted this real-world meta-analysis to compare the clinical efficacy and safety outcomes of SEV vs BEV in patients undergoing TAVR for aortic stenosis (AS).

Methods:
MEDLINE, EMBASE, and Scopus were queried to shortlist studies including AS patients undergoing TAVR. Primary outcomes included 30-day and 1-year all-cause and cardiac mortality. Secondary outcomes were permanent pacemaker implantation (PPI), paravalvular leak (PVL), aortic regurgitation (AR), stroke, major vascular complications (MVC), major bleeding (MB), acute kidney injury (AKI), myocardial infarction (MI), length of stay (LOS), patient prosthesis mismatch (PPM), and atrial fibrillation (AF). A random effects meta-analysis was conducted to derive risk ratios and mean differences with corresponding 95% confidence intervals (CI).

Results:
Our meta-analysis included 38 real-world studies. No significant association was seen in 30-day (RR=1.13, P=0.15) and 1-year all-cause mortality (RR=1.04, P=0.55), and cardiac mortality (RR=1.28, P=0.12). SEV was associated with a higher risk of 30-day PPI (RR=1.61, 95% CI 1.28-2.02, I2 = 88%, P<0.0001), mild PVL (RR=1.52, 95% CI 1.17-1.97, I2=76%, P=0.002), and moderate to severe PVL (RR=1.97, 95% CI 1.43-2.72, I2=51%, P<0.0001). Patients in the SEV group experienced more statistically significant AR (RR=1.72, 95% CI 1.29-2.30, I2=27%, P=0.0002), and 30-day MVC (RR=1.1, 95% CI 1.02-1.2, I2=0%, P=0.02) when compared to the BEV group. No statistically significant association was established for stroke, MB, AKI, MI, LOS, PPM, and AF.

Conclusion:
Our real-world analysis showed that SEV increases the risk of PPI, PVL, AR, and MVC. However, all-cause and cardiovascular mortality were comparable between both groups. Our results confirm the conclusions drawn from RCTs, thus reassuring decision-makers that these findings can be extrapolated to real-world populations.
Abstract 4140005: Trends in Stimulant-Involved Cardiovascular Disease Mortality, 1999 – 2023
Authors: Harris Rebecca Arden
Published: November 2024

Introduction:
Cocaine and methamphetamine, stimulants with potent central nervous system effects, are known to be cardiotoxic. They increase the risk of hypertension, coronary artery disease, coronary vasospasm, arrhythmias, cardiomyopathy, cardiac arrest, and stroke. Despite these well-documented risks, the National Survey on Drug Use and Health reports that illicit stimulant use is increasing.

Research Question:
How have mortality rates changed over time when cardiovascular disease (CVD) is the underlying cause of death and illicit stimulant use is a contributing factor?

Aims:
To describe trends in cardiovascular mortality rates from 1999-2023 and to stratify the analysis by race, ethnicity, sex, age, CVD subcategories, and stimulant type.

Methods:
We leveraged CDC WONDER data to model age-adjusted CVD mortality rates from 1999 to 2023 using joinpoint regression. For each stimulant type, demographic group, and CVD subcategory, we report annual percent changes (APCs) for each time segment and average annual percent changes (AAPCs) to estimate overall trend direction and magnitude.

Results:
From 1999 to 2023, stimulant-involved CVD mortality rates increased significantly, with an AAPC of 6.4%, contrasting sharply with the 2.0% decline in overall CVD mortality rates (Table). Each subcategory of CVD mortality (ischemic heart disease, hypertension; cerebrovascular disease) showed AAPC increases when stimulants were involved, with hypertensive diseases experiencing the largest AAPC rise at 9.1%.

Stratifying by drug type, methamphetamine-involved CVD death rates increased by 14.9% AAPC, compared to a 3.1% increase for cocaine-involved deaths. Demographic stratification revealed additional differences. Non-Hispanic White individuals had the highest AAPC (9.2%), followed by Asian/Pacific Islander (5.6%), Hispanic (5.4%), Non-Hispanic Black (3.0%), and American Indian/Alaskan Native individuals (1.9%). A higher AAPC also was observed among those aged ≥65 years (14.6%).

Conclusions:
Cardiovascular deaths where stimulants were a contributing cause have increased rapidly over the past 25 years despite the overall decline in the CVD mortality rate during the same period. The largest increases were seen in hypertensive diseases, methamphetamine-involved deaths, non-Hispanic White individuals, and older individuals. This study extends our understanding but is limited by potential inaccuracies in the recorded causes of death.
Abstract 4140035: Sex Differences in Nature History and Clinical Prognosis in Asymptomatic Significant Pulmonary Regurgitation Patients
Authors: Zhu Wenhao
Published: November 2024

Background:
There are limited data on the sex differences in the nature history and prognostic factors of asymptomatic pulmonary regurgitation (PR) patients.

Objectives:
This study aims to investigate the sex-specific differences in the nature history and clinical prognosis of PR.

Methods:
Asymptomatic PR patients undergoing cardiac magnetic resonance at our hospital between 2013 to 2023 were consecutively screened and followed until 2024; baseline characteristics and multimodality imaging variables at the first CMR examination time were assessed. The primary objective was the composite of cardiovascular death, cardiac hospitalization, and pulmonary valve replacement (PVR) events.

Results:
Overall, 173 males and 141 females were included. At baseline, females had lower QRS duration, right ventricular (RV) end-diastolic volume index (EDVi), and RV end-systolic volume index (ESVi) than males (All P < 0.05). The risk of the primary objective was higher in females (unadjusted HR: 1.697; 95% CI: 1.157, 2.489), it was even more pronounced after multivariable adjustment. This sexual disparity persisted in adult patients, irrespective of the primary diagnosis. Secondly, QRS > 160ms, RVESVi ≥ 80ml/m
2
, and RVEDVi ≥ 150ml/m
2
were not sex-specific, whereas RV eject fraction < 47% had predictive value only in females. Additionally, all risks related to these factors were higher in females.

Conclusion:
Females have a paradoxical increase in PVR events despite milder RV remodeling at baseline and they maintained a higher risk compared with males across longer QRS, larger RVEDVi and RVESVi, and lower RVEF; these findings suggested that this sexual disparity cannot be ignored when discussing thresholds.
Abstract 4140094: Prediction of Coronary Artery Calcium using Retinal Photographs via Deep Learning: Korean, Spanish and Indian populations
Authors: Tan Yong Yu , Correa Fabiano Ronaldo , Generoso Giuliano , Cho Jun Hwan , Choi Beom-hee , Cho Yunnie , Thakur Sahil , Rim Tyler Hyungtaek , Lee Chan Joo , Masip David , Barriada Ruben , Servat Olga , Hernandez Cristina , Cheng Ching-Yu , Savoy Florian , K R Nishanth , Rao Divya , Bensenor Isabela , Wong Tien Yin , Simo Rafael , Bittencourt Marcio
Published: November 2024

Introduction:
Cardiovascular diseases (CVD) are the leading cause of death in developed countries. Coronary artery calcium (CAC) is a clinically validated strong marker of CVD, and previous studies suggest that retinal blood vessels provide relevant information. This study aimed to validate the Reti-CVD model, developed for predicting CAC score through retinal photographs, using datasets from Spain, Korea and India.

Hypothesis:
We proposed the hypothesis that Reti-CVD model can accurately predict CAC scores from retinal photographs in the Spanish, Korean and Indian populations.

Methods:
The Reti-CVD model was applied to the Spanish Vall d'Hebron Institut de Recerca (VHIR) dataset (n=76), the Korean GreenCross Center dataset (n=3999), Korean Philip Screening Center dataset (n=5010) and the Indian population dataset (n=90). Key performance metrics were calculated to assess the model's effectiveness, including specificity, sensitivity, accuracy, and the area under the curve (AUC). Bootstrap replicates of 2000 were used to determine confidence intervals (CI) for the AUC, and the optimal thresholds were searched using Youden index method.

Results:
In the Spanish VHIR dataset, the Reti-CVD model showed strong predictive performance. The model achieved a specificity of 78.57%, sensitivity of 85.29%, and overall accuracy of 81.58%. The AUC was 0.8508, with a 95% CI of 0.7556-0.9307. In the Korean GreenCross dataset, the model achieved a specificity of 65.52%, sensitivity of 82.11%, and overall accuracy of 72.09%. The AUC was 0.8084, with a 95% CI of 0.7948-0.822. In the Korean Philip Screening Center dataset, the model achieved a specificity of 69.33%, sensitivity of 85.53%, and overall accuracy of 73.01%. The AUC was 0.845, with a 95% CI of 0.8329-0.8571. In the Indian population dataset, the model achieved a specificity of 55.77%, sensitivity of 75.00%. The AUC was 0.72.

Discussion:
The validation results indicate that the Reti-CVD model effectively predicts CAC scores using retinal photographs in the Spanish, Korean and Indian populations. These findings validate the model's robustness and generalizability and support the model's potential for non-invasive CVD risk screening within different ethnicities.
Abstract 4140179: Impact of COVID-19 on Patients With Hypertrophic Cardiomyopathy: Causes, Predictors, and Inpatient Mortality of 30-Day Readmission
Authors: Abood Zaid , Galazka Patrycja , Tajik A. Jamil , Jahangir Arshad , Jan M. Fuad
Published: November 2024

Background:
COVID-19 has led to significant global morbidity and mortality. Its impact on patients with hypertrophic cardiomyopathy (HCM) remains unclear.

Aim:
To evaluate the impact of COVID-19 infection on the readmission rate and associated outcomes in patients with HCM.

Methods:
In a retrospective study using the 2020 National Readmission Database, we collected data on patients with HCM who were admitted with the principal diagnosis of COVID-19. The primary outcome was the all-cause 30-day readmission rate. Secondary outcomes were common causes of readmission, in-hospital mortality, and resource utilization.

Results:
In 2020, a total of 1503 patients with HCM (mean age 67 years, 49% female) were hospitalized for COVID-19. Among them, 1216 (80.9%) were discharged alive and 180 (14.8%) were readmitted within 30 days. In-hospital mortality for readmissions remained relatively unchanged compared with index admissions (15.4% vs 19.0%, P=.34; Table 1). The most common cause of readmission was COVID-19 infection (38%), followed by other infections (11%) and acute kidney injury (4%). The most common cardiac cause for readmission was paroxysmal atrial fibrillation (2%). The mean length of stay for readmissions was relatively similar to the index admission (7.8 vs 9.9 days, P=.43). The mean hospital charge associated with readmission was $84,976 (total hospital charges were $15.2 million). The mean hospital cost associated with readmissions was $24,603 (total hospital costs were $4.4 million). A higher Charlson comorbidity index score was the main independent predictor of higher readmission rates.

Conclusions:
This study highlights the significant burden of COVID-19 on patients with HCM. Despite efforts to reduce readmission rates, a considerable percentage of patients experienced readmission within 30 days, largely attributed to COVID-19 infection. Close follow-up after discharge could prevent such readmission and the associated high mortality rates.
Abstract 4140380: Forecasting Heart Failure: Seasonal Alignment of Heart Failure Outcomes in New York
Authors: Gupta Prerna , Brinza Ellen , Khazanie Prateeti , Peterson Pamela , Ho Michael , Kao David
Published: November 2024

Background:
Seasonal variations have been observed in heart failure (HF) hospitalization. Our objective was to identify specific factors that could contribute to seasonal variability using a large longitudinal dataset of HF hospitalizations.

Methods:
Hospital discharge data was obtained for all hospitals in New York state from 1994-2007. Records with a primary diagnosis of heart failure. Year and month of admission were used as predictors to evaluate outcomes of in-hospital mortality, population-adjusted daily rate of hospital admissions, and length of stay (LOS) using univariable regression including a sinusoidal model to assess seasonality of HF outcomes. Observations were then adjusted for multiple medical covariables including acute diagnoses such as asthma, COPD, and pneumonia, average local monthly temperature, and humidity at each hospital using data from the Global Historical Climate Network to identify modifiers of seasonal variability.

Results:
Among 949,907 records, median age was 76 (IQR 65-84 years old), and 54% female (510,945 records). The population-adjusted rate of HF admissions increased by 1.1 admissions/day/year, whereas in-hospital mortality and LOS decreased by -0.3%/year and -0.3 days/year respectively (p<0.001 for all). Seasonal trends were identified for daily HF admissions (February peak, p<0.0001), mortality (January peak, p<0.001) and LOS (January peak, p<0.01). Cosinor analysis revealed significant periodicity for HF admission rate (amplitude ±0.9/admits/day/100,000 people, p<0.001), in-hospital mortality (amplitude ±0.47%, p<0.001), and LOS (amplitude ±0.23 days, p<0.01). No other patient characteristics were significant modifiers of seasonality. Odds of mortality were highest in July rather than January when adjusted for average local temperature but not humidity.

Conclusion:
Adverse outcomes in patients hospitalized with HF were significantly worse in winter months even when adjusted for concurrent diagnoses such as pneumonia. Local ambient temperature was the strongest modifier of the observed seasonality. Given increasing frequency of extreme weather events, additional work to determine mechanisms of this and other environmental risk factors is urgently needed.
Abstract 4140393: Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis
Authors: Amrute Junedh , Luo Xin , Penna Vinay , Yang Steven , Yamawaki Tracy , Hayat Sikander , Bredemeyer Andrea , Jung In-hyuk , Kadyrov Farid , Heo Gyu Seong , VENKATESAN RAJIU , Shi Sally , Parvathaneni Alekhya , Koenig Andrew , Kuppe Christoph , Baker Candice , Luehmann Hannah , Jones Cameran , Kopecky Benjamin , Zeng Xue , Blekwehl Tore , Ma Pan , Lee Paul , Terada Yuriko , Fu Angela , Furtado Milena , KREISEL DANIEL , Kovacs Attila , Stitziel Nathan , Jackson Simon , Li Chi-Ming , Liu Yongjian , Rosenthal Nadia , Kramann Rafael , Ason Brandon , Lavine Kory
Published: November 2024

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored, and there are currently no approved treatments that directly target cardiac fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 45 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. We lineage traced FAP fibroblasts
in vivo
and showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different
in vivo
mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches.
In vivo
, we deleted the IL-1 receptor on fibroblasts, the IL-1 ligand in CCR2 monocytes and macrophages, and inhibited IL-1 signaling using a monoclonal antibody and showed fewer pro-fibrotic fibroblasts, decreased cardiac fibrosis, and improved cardiac function. Herein, we characterize fibroblast lineage diversification in the failing heart and showed a subset of macrophages signal to fibroblasts via IL-1 and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.
Abstract 4140454: The Outcome of Restrictive Cardiac Allograft Physiology in Severe Coronary Allograft Vasculopathy
Authors: Tsuji Masaki , Patel Jignesh , Kittleson Michelle , Chang David , Kransdorf Evan , Nikolova Andriana , Stern Lily , Bhatnagar Nayana , Kobashigawa Jon
Published: November 2024

Background:
Microvascular dysfunction after heart transplantation leads to restrictive cardiac allograft physiology (RCP), which is classified to severe coronary allograft vasculopathy (CAV); however, the prognosis of RCP remains unclear. This study aimed to elucidate the prognosis of RCP in comparison with that of severe angiographic CAV.

Methods:
We assessed patients with RCP defined as mean right atrial pressure >12 mmHg, pulmonary capillary wedge pressure >25 mmHg, and cardiac index <2.0 L/min/m
2
who underwent heart transplantation between 2004 and 2023. The primary outcome was death or re-transplantation.

Results:
Of the 116 patients with severe CAV, 42 had RCP (RCP-CAV group) and 74 had severe angiographic CAV without RCP (Angio-CAV group). A significantly shorter time from heart transplantation to diagnosis and lower subsequent percutaneous catheter intervention after diagnosis were seen in the RCP-CAV group than in the Angio-CAV group (both p<0.001). The incidence of death or re-transplantation within 5 years after was significantly higher in the RCP-CAV group than in the Angio-CAV group (69.0% vs 50.0%, p=0.047). Freedom from death or re-transplantation at 5 years was significantly worse in the RCP-CAV group compared to the Angio-CAV group (18.4% vs 35.4%, p=0.001). In the Cox proportional hazard model, RCP was independently associated with an increased risk of death or re-transplantation (Hazard ratio 2.08, 95% Confidence intervals 1.26-3.44, p=0.004).

Conclusions:
The prognosis of patients with RCP was significantly worse than that of patients with severe angiographic CAV. The early detection of microvascular dysfunction and re-transplantation listing may improve the prognosis of patients with RCP.
Abstract 4141725: Abnormal day-night blood pressure and systemic hemodynamics in heart failure compared to normotension and controlled hypertension
Authors: Srungavarapu Sambasiva Rao , Khatri Chander , Osmond Peter , Izzo Joseph
Published: November 2024

Background:
High night-time BP and heart rate (HR) and insufficient decreases (“non-dipping”) in night-time BP and HR are markers of high morbidity and mortality. Non-dipping has been reported in some patients with hypertension (HT) or history of acute heart failure (HF) but the underlying derangements in ambulatory systemic hemodynamics have not been described.

Aims:
Present studies were undertaken to confirm whether patients with history of HF have abnormal dipping of BP and HR and to identify potential differences between day and night ambulatory hemodynamics in HF, normotensives (N), and controlled HT (C-HT, 24-hr systolic BP<135 mHg).

Methods:
Ambulatory BP-pulse wave readings (PWA, ARCSolver/Mobil-O-Graph) were taken every 20 minutes for 24 hrs, with day and night values averaged. Variables of interest included systolic and diastolic BP (SBP and DBP), HR, cardiac index (CI), stroke volume index (SVI), and total vascular resistance index (TVRI). Groups were compared by ANOVA/Bonferroni. HF patients were further characterized by echo ejection fraction (EF) as preserved (HFpEF) or reduced (<40%, HrEF).

Results:
Data were obtained from 138 individuals (N 39, C-HT 63, and HF 36); main results are summarized in the Table. Night SBP was higher in HFpEF than HFrEF but both had persistently low SVI and high HR and TVRI. In those with echo and ambulatory PWA studies within 6 months, SVI did not correlate with EF.

Conclusions:
HF patients, irrespective of EF, often have nocturnal hypertension (night-time SBP
>
120) and high HR compared to N and C-HT; they also have blunted nocturnal dipping of BP and HR. These findings suggest that 24-hr ambulatory BP-PWA monitoring may be of value in routine HF management. Our study also shows that ambulatory PWA is feasible in HF patients and that everyday hemodynamic patterns in HF differ from N and C-HT; HF patients, irrespective of EF, are characterized by persistently low SVI and persistently high HR and TVRI throughout the day and night, a pattern consistent with excessive sympathetic nervous overactivity. Further studies are necessary before recommending routine systemic hemodynamic assessment in HF.
Abstract 4145373: PREVALENCE OF NON-RHEUMATIC MITRAL STENOSIS IN CHRONIC KIDNEY DISEASE: NATIONAL IN-PATIENT SAMPLE ANALYSIS
Authors: Joseph Varughese Vivek , Mathews Hella Fiona
Published: November 2024

Background:
There have been several studies postulating the association between Mitral valve stenosis (MS) and Chronic Kidney Disease (CKD). Accelerated calcification of the mitral valve is the postulated pathophysioloigcal mechanism.

AIM/ RESEARCH QUESTION

Aim of the study is to analyze the prevalence of non-rheumatic mitral stenosis (MS) in patients with CKD and End Stage Renal Disease (ESRD) and to assess the association between the conditions.

Methods:
Using the National In-Patient Sample (NIS) 2019, admissions with documented CKD and ESRD were identified. The prevalence of non rheumatic Mitral stenosis (MS) in the admission cohort was analyzed. Chi-square test was used to analyze the association between the two conditions.

RESULTS:
We identified 4329 admissions with overlapping diagnoses of non-rheumatic MS and CKD, and 905 admissions with overlapping diagnoses of non-rheumatic MS and ESRD. The prevalence of MS in admissions with the diagnosis of CKD was 43.33% (41.14 – 45.84). Prevalence of MS in admissions with ESRD was 56.07% (49.24 - 64.31). There was significant association between MS and CKD, noted with an Odds ratio of 4.14 (3.78 – 4.52, p=0.00) and also between diagnoses of MS and ESRD: Odds ratio of 3.18 ( 2.73 -3.70, p=0.00). (TABLE 1)

Conclusions:
Based on our analysis, nearly half of the admissions with documented CKD and ESRD did have diagnosis of Mitral stenosis. The association between the conditions was statistically significant.
Abstract 4145438: Pharmacological Targeting of FAS Attenuates Macrophage-Derived Foam Cell Formation
Authors: Ibrahim Dina , Hafezi Shahab , Belaygorod Larisa , Arif Batool , Semenkovich Clay , Zayed Mohamed
Published: November 2024

Introduction:
Fatty acid synthase (FAS), a key enzyme in
de novo
lipogenesis, may contribute to the pathogenesis of atherosclerosis. Notably, the circulating form of FAS (cFAS) is a potential biomarker for peripheral arterial disease and carotid artery stenosis, particularly in patients with diabetes. Within the atherosclerotic lesion, macrophage-derived foam cells (MDFc) play a crucial role in disease pathogenesis.

Research question:
This study addressed the role of cFAS in macrophage-derived foam cell formation and the efficacy of FAS inhibitors in mitigating this process.

Methods:
Cell culture:
U937 monocytes were differentiated into macrophages using PMA (200ng/mL) for 24h.
Foam Cell Assay:
Differentiated macrophages were cultured under various conditions. The RPMI1640 media supplemented with 5% FBS used as a negative control. To induce MDFc, some cultures used 5% human serum containing high FAS/low LDL levels as a positive control. Other cultures combined human serum containing low FAS with high, medium, or low LDL levels. Additionally, the effects of FAS inhibitors were tested by adding PTM (20μM), TVB-2640 (100nM), or GSK2194069 (10nM) to the media for 48h, both with and without high FAS/low LDL levels.
Oil-O-Red Staining:
Lipid droplets were quantified after neutral lipid staining with Oil-O-Red.

Results:
Our findings reveal a notable increase in the formation of MDFc when macrophages were cultured with high FAS/low LDL levels as compared to the low FAS/low LDL condition (P=0.00082) and as compared to the negative control using 5% FBS (P=0.0001). Furthermore, we observed a significant reduction in lipid droplets within MDFc following treatment with FAS inhibitors. Both the selective FAS inhibitors TVB2640 and GSK2194069 led to significant reductions in MDFc (P<0.0001).

Conclusion:
Our findings underscore the potential role of FAS in promoting the formation of MDFc. Pharmacological inhibition of FAS can mitigate foam cell formation, which represents a potential novel avenue for clinical management of atherosclerosis. Further exploration of the mechanism of action of pharmacological targeting of extracellular cFAS versus intracellular FAS in pre-clinical
in vivo
models is warranted.
Abstract 4145445: Sex Differences in Time from Referral to Procedure, Functional Capacity, and Quality of Life Improvement After Transcatheter Aortic Valve Replacement
Authors: Singhal Meghali , Jones Bryce , Gul Maha , Yim Samantha , Shafer Colin , Baay Peter , Tedesco Dominic , Ahmed Bina , Shenoda Michael , Aragon Joe
Published: November 2024

Background:
Transcatheter aortic valve replacement (TAVR) has been shown to improve survival and quality of life (QOL). The Kansas City Cardiomyopathy Questionnaire (KCCQ) monitors four domains of valvular heart disease (physical limitation, symptom frequency, social limitation, and QOL) before and after TAVR, yielding an overall summary score (KCCQ-OS). Prior studies have acknowledged sex-based discrepancies in baseline health status prior to TAVR, such as older age and fewer cardiovascular comorbidities among females. However, time from initial referral to procedure date may contribute to sex-based differences in KCCQ-OS before and after TAVR.

Methods:
We compared differences between pre-procedure and post-procedure KCCQ-OS, assessed at 30-day and 1-year follow-up in 649 patients (353 males and 296 females) who underwent TAVR at Santa Barbara Cottage Hospital between 2015 and 2024. We also examined differences in baseline patient characteristics including age, co-morbidities, and time to procedure from initial referral date.

Results:
Females were older and had a higher prevalence of hypertension compared to males (80.1% vs 78.8%) but lower prevalence of all other traditional cardiovascular comorbidities. Females had significantly lower baseline KCCQ-OS compared to males (56.17 ± 26.01 vs 61.58 ± 26.09, p = 0.003) (Figure 1). Compared to baseline scores, all patients had significant increases in their scores at post-TAVR 30-day and 1-year follow-up (p < 0.001) (Figure 1). At both 30-day and 1-year follow up, males had higher KCCQ-OS compared to females [(87.37 ± 16.55 vs 84.24 ± 16.91, p = 0.009), (87.87 ± 16.61 vs 85.42 ± 17.82, p = 0.04)] (Figure 1). Time to TAVR (days) from initial referral was significantly higher not only in patients under the age of 80 (p = 0.01) but also in females compared to males (p = 0.02) (Figure 1).

Conclusion:
Females consistently had lower KCCQ-OS at baseline and post-TAVR, indicating measurements of lower functional capacity and quality of life compared to males. Despite fewer comorbidities at baseline, the impact of delays from referral to procedure data among females may contribute to lower KCCQ-OS before and after TAVR.
Abstract 4145489: Serum Proteomics Approach to Identify the ‘Hepatic Factor’ Causing Pulmonary Arteriovenous Malformations Post-Glenn Shunt
Authors: Gonzalez-Teshima Laura , Hakamada Keisuke , Ikeda Tadashi , Murata Kozue , Minatoya Kenji , Masumoto Hidetoshi
Published: November 2024

Introduction:
Pulmonary Arteriovenous Malformations (PAVMs) are a main surgical complication of second-stage palliative Glenn shunt for single ventricle. PAVMs lead to early mortality. Currently there is no available treatment as its physiopathology remains unknown.

Hypothesis:
This study hypothesizes that hepatic-derived factor causing PAVMs could be proteome-derived.

Goals:
To discern differences in proteomic profiles of patient-paired serum from superior vena cava (SVC) and hepatic vein (HV) as a preliminary approach to identify PAVM-related hepatic vein blood-enriched factors.

Methods:
Paired full blood samples were collected from SVC and HV origin during routine cardiac catheterization of patients with diverse cardiac congenital malformations from 0 to 1 years of age (n=3). Serum was extracted and high abundant proteins were depleted. Single-pot solid-phase-enhanced sample preparation method and trypsinization digestion coupled with label-free data-dependent acquisition liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was performed. Subgroup differential expression analysis by abundance ratio (SVC/HV) (Adj. P-Value<0,05) was used to identify differentially upregulated proteins uniquely expressed in HV. Proteins with only one unique peptide identifier were discarded. Gene ontology biological analysis and functional pathways analysis were performed using PANTHER.

Results:
Differential proteomic profiles were evidenced according to serum origin. 4706 peptides coding for 605 common proteins, 68 unique proteins to SVC and 110 unique for HV were identified. From 50 protein coding genes found upregulated in HV sample (P<0,05), 16 had >1 unique peptide identifier and 5 were found to be uniquely expressed in HV. Overrepresentation of integrin signaling pathway was identified (fold enrichment 21.56, FDR P=0,0265) related to these 16 HV upregulated expression genes.

Conclusion:
Serum proteomic profile per sample origin analysis is promising for understanding PAVM physiopathology. Functional gene ontology pathway associating integrin signaling pathway enhancement in HV proteome, known to play a role in vascular anomalies, may serve as a first milestone for the “hepatic-factor” identification. Further validation experiments are required.
In vitro
induced pluripotent stem cell PAVM proof-of-concept model is under development.
Abstract 4145510: SLIT2 is a novel driver of doxorubicin cardiotoxicity through adipose-cardiac crosstalk
Authors: Ozcan Mualla , Lotfinaghsh Aynaz , Valenzuela Ripoll Carla , Diab Ahmed , Guo Zhen , Jia Wentong , Ataran Anahita , Hajirezaei Hamidreza , Pedersen Lauren , Sargazi Alireza , Razani Babak , Lu Weining , Asnani Aarti , Chirinos Julio , Bergom Carmen , Lodhi Irfan , Brestoff Jonathan , MITTENDORFER Bettina , Javaheri Ali
Published: November 2024

Background:
Dox cardiomyopathy remains a clinically significant problem. Alternate-day fasting has been shown to exacerbate Dox cardiomyopathy and cachexia. We sought to identify common disease mechanisms by comparing proteomics in mice vs. humans with Dox cardiomyopathy.

Methods:
Chow-fed C57BL/6 male mice (n=50) were treated with Dox (5 mg/kg intraperitoneal x 3 doses). One day after the last dose, mice were randomized to ad-lib feeding or ADF (24 hours of fasting followed by 24 hours of refeeding) for two weeks, followed by echocardiography, and body composition analysis. For aptamer-based human proteomics, we utilized banked blood from patients with Dox cardiomyopathy (n=47) and other cardiomyopathy (n=2167) from the Penn Heart Failure Study. For 2 group comparisons in mice and humans, we used Student’s t-test and false-discovery rate adjusted for covariates, respectively. For 3-group analyses, one-way ANOVA with Sidak’s correction for multiple comparisons was utilized.

Results:
Alternate-day fasting (ADF) decreased left ventricular (LV) ejection fraction (p=0.047, 95% CI of difference: -5.61 to -0.04) and LV mass (p=0.012, 95% CI of difference: -10.10 to -1.39) and increased end-diastolic volume/body weight (p=0.035, 9.5% relative reduction) in mice treated with Dox. Dox+ADF also increased adiposity (p=0.005, 95% CI of difference: 6.266 to 29.52) and brown adipose mass (p<0.001, 95% CI: 1.231 to 3.206). Aptamer-based plasma proteomics showed that Dox+ADF upregulated SLIT2, which was the most significant and pronounced protein identifying human Dox cardiomyopathy (vs other cardiomyopathies, p<0.0001, 95% CI of difference: 20307 to 25447). Furthermore, Dox+ADF stimulated SLIT2 and its target UCP1 in inguinal adipose tissue, while UCP1 knockout attenuates Dox cardiotoxicity. Further studies showed that SLIT2 was both necessary and sufficient for Dox cardiotoxicity.

Conclusion:
These findings suggest that adipose-cardiac crosstalk mediated by SLIT2 is a novel mechanism of Dox cardiomyopathy.
Abstract 4145528: Right Atrial Pressure Respiratory Variation as a Predictor of Right Heart Failure After Left Ventricular Assist Device
Authors: Buchanan Cole , Lamicq Melissa , Atteya Miriam , Lateef Azalfa , Read Jacob , Rao Vishal N. , Friedman Samuel , Biscopink Alec , Kilic Arman , Hajj Jennifer , Wehbe Ramsey , Houston Brian , Tedford Ryan
Published: November 2024

Introduction:
Right heart failure (RHF) is a significant contributor to morbidity and mortality after left ventricular assist device (LVAD) implantation. Lack of respiratory variation in the right atrial pressure (RAP) waveform, perhaps a marker of RV reserve capacity, has been associated with RHF and worse outcomes in patients with left heart failure and precapillary pulmonary hypertension. It is unknown if RAP respiratory variation may predict early RHF post-LVAD implantation.

Hypothesis:
We hypothesized that lack of RAP respiratory variation pre-implant would be predictive of early post-LVAD RHF.

Methods:
In this single center retrospective analysis, pre-LVAD right heart catheterizations for 183 patients who underwent HeartMate 3 LVAD implantation between November 2016 and December 2023 were reviewed. RAP and pulmonary artery wedge pressure (PAWP) respiratory variation were independently quantified by two investigators. Lack of RAP respiratory variation was defined as ≤ 2 mmHg between inspiration and expiration. To account for differences in respiratory effort and pulmonary vascular compliance, the difference between PAWP and RAP respiratory variation was assessed. The 2020 Academic Research Consortium definition was used to define early RHF. Groups were compared using Mann-Whitney U test and Fisher’s exact test.

Results:
Sixty-two of 183 patients (34%) developed early RHF post-LVAD. RAP was similar between the no RHF and RHF groups (10.4±6.4 vs. 10.5±6.8, p=0.98). There was no significant difference in RAP respiratory variation between the no RHF and RHF groups (3.2±2.4 vs. 3.0±2.0, p= 0.55). There was no difference in RHF rates between those that lacked and maintained RAP respiratory variation (35% vs. 32%, OR = 0.86, 95% CI [0.47, 1.60]). The difference between PAWP and RAP respiratory variation was not significantly different between no RHF and RHF groups (4.3±2.8 vs. 4.7±3.2, p = 0.41).

Conclusion:
Despite the prognostic significance in heart failure and precapillary pulmonary hypertension populations, RAP respiratory variation was not associated with post-LVAD RHF in our study. Ongoing efforts are needed to improve prediction of RHF in patients undergoing durable LVAD implantation.
Abstract 4145554: Obstructive Sleep Apnea Increases the Risk of Cardiovascular Disease and Stroke Among Persons with Cancer: Analyses from a Multi-center Electronic Healthcare Records-Based Database.
Authors: Aneni Ehimen , Ahmed Omair , Otite Fadar
Published: November 2024

Background:
Cancer and obstructive sleep apnea (OSA) individually elevate cardiovascular diseases (CVD) and stroke risk. However, it is unclear whether OSA contributes additional CVD risk in persons with pre-existing cancer.

Methods:
Using the TriNetX, an electronic healthcare records-based database from large healthcare organizations, we compared adverse CVD outcomes and ischemic stroke incidence between patients with and without OSA diagnosed with cancer between 01/2012 and 06/2023. Adverse CVD outcomes was defined as a composite of incident heart failure, incident atrial fibrillation / flutter, incident myocardial infarction or all-cause mortality. Patients were eligible to enter the cohort on the day of cancer diagnosis. The follow-up period for outcome events began one year after patients entered the cohort and patients contributed follow-up time till the outcome event occurred or till the end of the study period.

After propensity risk score matching on demographics and comorbidities we conducted a time-to-event analyses.

Results:
A total of 509,477 patients with both cancer and OSA were propensity score matched to 509,477 patients with cancer but without OSA. The table shows the demographic and comorbidities of the matched groups. Among persons with cancer, OSA diagnosis was associated with increased risk of adverse CVD outcomes (HR: 1.37, 95% CI: 1.36 – 1.38). OSA in persons with cancer increased the risk of heart failure, atrial fibrillation / flutter and myocardial infarction. OSA also increased the risk of ischemic stroke. However, total mortality risk was reduced among those with OSA. See the table for details.

Conclusion:
OSA increases the risk of adverse CVD outcomes and ischemic stroke in persons with cancer. These analyses suggest that persons with cancer should be screened and treated for OSA. Future studies will need to determine the impact of OSA treatment e.g., positive airway pressure (PAP) therapy on CVD related outcomes in persons with cancer. Further investigation into the paradoxical reduction in all-cause mortality with OSA is warranted.